Bibliography, page 5

1. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36479909
   KMT2A-D pathogenicity, prevalence, and variation according to a population database.

   Larson JK, Hunter-Schlichting DN, Crowgey EL, et al. · Cancer Med 2023
   used by KMT2B (MLL2/MLL4) - the other protein menin binds, and the one this graph never wrote
2. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 37142882
   KMT2D Deficiency Promotes Myeloid Leukemias which Is Vulnerable to Ribosome Biogenesis Inhibition.

   Xu J, Zhong A, Zhang S, et al. · Adv Sci (Weinh) 2023
   used by KMT2D (MLL2/MLL4) - the gene named in this graph's menin-resistance entry, written here for the first time
3. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
   International Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory HEMatological Malignancies in Children, Subprotocol D: Trametinib + Dexamethasone + Cyclophosphamide and Cytarabine in Pediatric Patients With Relapsed or Refractory Hematological Malignancies

   HEM iSMART consortium · ClinicalTrials.gov 2023
   used by KRAS - the commonest co-mutation in a disease that has almost none, and it is usually in a minority of the cells
4. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36763502
   A fetal tumor suppressor axis abrogates MLL-fusion-driven acute myeloid leukemia.

   Eldeeb M, Yuan O, Guzzi N, Thi Ngoc PC, Konturek-Ciesla A, Kristiansen TA, Muthukumar S, Magee J, Bellodi C, Yuan J, Bryder D · Cell Rep 2023
   used by LIN28B has THREE published signs in myeloid leukaemia - oncogene, tumour suppressor, and differentiation agent - and the design quality runs opposite to the direction the index-fusion story needs, LIN28B has two routes - blocking let-7, and binding mRNAs directly - and in KMT2A::AFF1 every published mechanism is the direct-mRNA one (let-7 IS measured in mouse MLL-fusion AML: in-session correction), MYBBP1A - the let-7-independent effector through which LIN28B suppresses MLL-rearranged AML, and a nucleolar MYB co-repressor that reads H3K9me2, PROPOSED: measure let-7 and restore it in the human fetal-liver KMT2A::AFF1 model - an axis measured in mouse MLL-fusion AML but never in the index fusion, The fetal state is PERMISSIVE for lymphoid KMT2A-fusion transformation and PROTECTIVE against myeloid - which is why LIN28B has opposite signs in the two literatures, Two groups invoke LIN28B to explain the SAME epidemiological fact in OPPOSITE directions - and neither claim is the one this graph has been repeating
5. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 37148657
   Targeting MYC in combination with epigenetic regulators induces synergistic anti-leukemic effects in MLLr leukemia and simultaneously improves immunity.

   Fitzel R, Secker-Grob KA, Keppeler H, Korkmaz F, Schairer R, Erkner E, Schneidawind D, Lengerke C, Hentrich T, Schulze-Hentrich JM, Schneidawind C · Neoplasia 2023
   used by MAT2A - the enzyme that makes the methyl donor, and the one metabolic dependency in this disease with two independent papers and a lymphoid PDX result
6. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 37523546
   MBTD1 preserves adult hematopoietic stem cell pool size and function

   Takubo K, Htun PW, Ueda T, et al. · Proceedings of the National Academy of Sciences of the USA 2023
   used by MBTD1 - the H4K20me1/me2 reader inside NuA4/TIP60, the quiescence brake on adult haematopoietic stem cells, and the 3' partner of ZMYND11::MBTD1 whose methyl-lysine cage the fusion carries and does not use
7. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 36852638
   MED26-containing Mediator may orchestrate multiple transcription processes through organization of nuclear bodies.

   Suzuki H, Furugori K, Abe R, Ogawa S, Ito S, Akiyama T, Horiuchi K, Takahashi H · Bioessays 2023
   used by MED26 — a common-essential Mediator subunit with a solved 87-residue domain and no ChEMBL target entity at all
8. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36789545
   Pathologic, cytogenetic, and molecular features of acute myeloid leukemia with megakaryocytic differentiation: A report from the Children's Oncology Group

   Chisholm KM, Smith J, Heerema-McKenney AE, Choi JK, Ries RE, Hirsch BA, et al., Kahwash SB · Pediatric Blood and Cancer 2023
   used by Megakaryocyte — the platelet factory whose loss causes the bruising that brings these children in, and which also holds stem cells still, Megakaryocyte-erythroid progenitor (MEP) — the branch KMT2A fusions almost never take, which is why it was a usable control
9. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.reviewPMID 37280427
   Gut microbiome immaturity and childhood acute lymphoblastic leukaemia

   Peppas I, Ford AM, Furness CL, Greaves MF · Nature Reviews Cancer 2023
   used by Mel Greaves (Centre for Evolution and Cancer, ICR London) — natural history, in-utero origin and the prevention question
10. speculative confidence 1 of 5: Our own inference or analogy. Not shown to be true.paperPMID 37291166
    Investigating the novel-binding site of RPA2 on Menin and predicting the effect of point mutation of Menin through protein-protein interactions.

    Kaur G, Prajapat M, Singh H, Sarma P, Bhadada SK, Shekhar N, Sharma S, Sinha S, Kumar S, Prakash A, Medhi B · Scientific Reports 13(1):9337 2023
    used by Menin binds RPA2 directly, the contact maps to RPA2 aa 43-171 across its low-affinity ssDNA site, and three MEN1 patient missense mutations abolish it - a 2003 finding that this graph had never cited despite menin being its central node
11. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36795828
    Menin "reads" H3K79me2 mark in a nucleosomal context.

    Lin J, Wu Y, Tian G, Yu D, Yang E, Lam WH, Liu Z, Jing Y, Dang S, Bao X, Wong JWH, Zhai Y, Li XD · Science 2023
    used by Menin's nucleosome grip (8GPN): a three-patch surface at menin 353-362, 428-442 and 556-587 that holds H3, H4 and H2B - and touches H2A at exactly one residue
12. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 37480164
    Children's Oncology Group's 2023 blueprint for research: Myeloid neoplasms

    Cooper TM, Alonzo TA, Tasian SK, et al. · Pediatric Blood & Cancer 2023
    used by Myeloid-directed antigens (CD33, CD123) — the only immunotherapy axis that survives lineage switch
13. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 37428633
    Cyclin E/CDK2 and feedback from soluble histone protein regulate the S phase burst of histone biosynthesis.

    Armstrong C, Passanisi VJ, Ashraf HM, et al. · Cell Reports 2023
    used by NASP - the soluble histone reservoir, and the only gene in this beat with a real selective difference at a pan-essentiality shallow enough to interpret
14. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 36930688
    The histone chaperone NASP maintains H3-H4 reservoirs in the early Drosophila embryo.

    Tirgar R, Davies JP, Plate L, et al. · PLoS Genetics 2023
    used by NASP - the soluble histone reservoir, and the only gene in this beat with a real selective difference at a pan-essentiality shallow enough to interpret
15. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36927643
    Inhibition of KDM7A/B histone demethylases restores H3K79 methylation and protects against osteoarthritis.

    Assi R, Cherifi C, Cornelis FMF, et al. · Ann Rheum Dis 2023
    used by Nobody has convincingly found the H3K79 eraser - and that constraint sets the clock on every DOT1L inhibitor
16. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36455613
    Mutant NPM1 Directly Regulates Oncogenic Transcription in Acute Myeloid Leukemia

    Uckelmann HJ, Haarer EL, Takeda R, Wong EM, et al. · Cancer Discov 13(3):746-765 2023
    used by NPM1 (nucleophosmin) — the nucleolar shuttle whose mutant form binds chromatin with KMT2A and buys the second menin-inhibitor indication
17. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.journal-articlePMID 36861410
    KMT2A partner genes in infant acute lymphoblastic leukemia have prognostic significance and correlate with age, white blood cell count, sex, and central nervous system involvement: a Children's Oncology Group P9407 trial study

    · Haematologica 2023
    used by Papers we know exist, know matter, and cannot read, WBC 300: a stratification convenience, not a biological threshold - and the evidence says so four different ways, What this beat searched, what it rejected, and the two papers it could not read - after a fifth route rescued the third, Where KMT2A-rearranged leukemia physically sits — marrow niche, CNS, blood, liver/spleen and skin
18. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 37075125
    RNA binding induces an allosteric switch in Cyp33 to repress MLL1-mediated transcription.

    Blatter M, Meylan C, Clery A, et al. · Sci Adv 2023
    used by PHD3 and the CyP33 RRM: Kd 7-15 uM, and a 2023 ternary structure that settles the 2010 disagreement - H3K4me3 and the RRM CAN be held at once, and the real switch is RNA, What is lost: the PHD3/CYP33 switch that lets wild-type KMT2A turn itself off, What was searched for a structure and what came back empty: the KMT2A interface layer enumerated by accession pair, with the graph's own unmapped interfaces listed
19. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
    PDB 7ZEZ: Trimolecular complex Cyp33-RRMdelta alpha : MLL1-PHD3 : H3K4me3

    Blatter M, Meylan C, Clery A, et al. · RCSB Protein Data Bank 2023
    used by PHD3 and the CyP33 RRM: Kd 7-15 uM, and a 2023 ternary structure that settles the 2010 disagreement - H3K4me3 and the RRM CAN be held at once, and the real switch is RNA
20. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 37601865
    Monocytic and blastic plasmacytoid dendritic cell differentiation in acute leukemia with KMT2A rearrangement

    Xue O, Curry CV, Fang H, Bueso-Ramos CE, Medeiros LJ, Wang W · eJHaem 2023
    used by Plasmacytoid dendritic cell — the interferon cell that KMT2A-rearranged leukaemia occasionally becomes, and is more often mistaken for
21. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 37946878
    A Case of Acute Myeloid Leukemia Mimicking Blastic Plasmacytoid Dendritic Cell Neoplasm: Utility of the Proposed Upcoming WHO-5 Diagnostic Criteria

    Jhajj B, Henrie R, El-Khalidy Y, Moshref Razavi H · Case Reports in Hematology 2023
    used by Plasmacytoid dendritic cell — the interferon cell that KMT2A-rearranged leukaemia occasionally becomes, and is more often mistaken for
22. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 37756159
    Principles of assembly and regulation of condensates of Polycomb repressive complex 1 through phase separation

    Brown K, Chew PY, Ingersoll S, Espinosa JR, Aguirre A, Espinoza A, Wen J, Astatike K, Kutateladze TG, Collepardo-Guevara R, Ren X · Cell Reports 2023
    used by Polycomb bodies — indirect evidence via CBX8, undercut by the finding that CBX8-PRC1 condensates are dissolved rather than built by the rest of PRC1
23. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36510685
    Prednisolone pharmacokinetics after oral prednisone administration in paediatric patients with kidney transplant.

    de Truchis C, Bouazza N, Foissac F, Charbit M, Dehoux L, Lui G, et al. · Br J Clin Pharmacol 2023
    used by Prednisone - the prophase drug, the prognostic factor, and a prodrug that has never itself been tested on a KMT2A-rearranged blast
24. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 38061017
    Proteogenomic analysis reveals cytoplasmic sequestration of RUNX1 by the acute myeloid leukemia-initiating CBFB::MYH11 oncofusion protein

    · Journal of Clinical Investigation 2023
    used by Proximity-labelling map of KMT2A::AFF1 — the experiment nobody has run in twenty years of interactome work, The fusion-oncoprotein TurboID experiment this graph proposes has already been published - for PML::RARA, RUNX1::RUNX1T1, CBFB::MYH11, NUP98::HOXA9 and SET::NUP214, and not for any KMT2A fusion
25. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 37951487
    Lycorine eliminates B-cell acute lymphoblastic leukemia cells by targeting PSAT1 through the serine/glycine metabolic pathway.

    Liu Y, Du Z, Li T, et al., Chen C · Eur J Pharmacol 2023
    used by PSAT1 (Q9Y617) - a DIRECT ATF4 target, and the gene that shows the brief's menin-selectivity claim was PHGDH's and not the pathway's, The one experiment that settles this beat: dose-matched menin and DOT1L arms in RS4;11 with H3K4me3 ChIP at PHGDH, plus 13C-serine flux - and it answers the cycle-58 question at the same time
26. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 37534584
    Cohesin Subunit RAD21 Regulates the Differentiation and Self-Renewal of Hematopoietic Stem and Progenitor Cells.

    Kumar P, Zhang N, Lee J, Cheng H, Kurtz K, Conneely SE, Sasidharan R, Rau RE, Pati D · Stem Cells 2023
    used by RAD21 - the cohesin subunit with the most break-prone sites in KMT2A-rearranged patients, and the degron experiment this graph keeps asking for
27. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 37794136
    Bone Marrow Failure and Immunodeficiency Associated with Human RAD50 Variants.

    Takagi M, Hoshino A, Bousset K, et al. · Journal of Clinical Immunology 2023
    used by RAD50 (Q92878, 1312 aa) - the third MRN subunit, and the one that settles whether the complex is incoherent in DepMap: mean -0.114 with 5.2% of 1,257 lines below -0.5, so it sits with NBN and not with MRE11, yet it covaries with MRE11 across cell lines as tightly as BRCA1 does with BARD1
28. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36453114
    Repurposing immunosuppressants for antileukemia therapy.

    Sezaki M, Huang G · EMBO Mol Med 2023
    used by Repurposing approved IMPDH inhibitors (mycophenolate, mizoribine, ribavirin) in KMT2A-rearranged leukaemia - cheap, mechanistically attractive, and asking an immunosuppressant of a neutropenic infant
29. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 37000624
    SATB1 regulates 3D genome architecture in T cells by constraining chromatin interactions surrounding CTCF-binding sites

    Wang B, Ji L, Bian Q · Cell Rep 2023
    used by SATB1 - a nuclear-matrix and PML-body genome organiser with its own matrix-targeting sequence, the clearest subnuclear-localization entry in this beat, and a T-lineage factor that B cells do not need
30. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 37544964
    A dual function for the chromatin organizer Special A-T rich Binding Protein 1 in B-lineage cells

    Thomas M, Bruzeau C, Martin OA, Pollet J, Bender S, Carrion C, et al. · Cell Mol Immunol 2023
    used by SATB1 - a nuclear-matrix and PML-body genome organiser with its own matrix-targeting sequence, the clearest subnuclear-localization entry in this beat, and a T-lineage factor that B cells do not need
31. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 37756522
    A human genome editing-based MLL::AF4 ALL model recapitulates key cellular and molecular leukemogenic features

    Bueno C, Torres-Ruiz R, Velasco-Hernandez T, Molina O, Petazzi P, Martinez A, Rodriguez V, Vinyoles M, Cantilena S, Williams O, Vega-Garcia N, Rodriguez-Perales S, Segovia JC, Quintana-Bustamante O, Roy A, Meyer C, Marschalek R, Smith AL, Milne TA, Fraga MF, Tejedor JR, Menéndez P · Blood 142:1752-1756 2023
    used by Separation-of-function test: does KMT2A::AFF1 need its C-terminal homology domain to dimerise?
32. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 37190162
    Set Protein Is Involved in FLT3 Membrane Trafficking.

    Marcotegui N; Romero-Murillo S; Marco-Sanz J; Peris I; Berrozpe BS; Vicente C; Odero MD; Arriazu E · Cancers (Basel) 2023
    used by SET / TAF-I beta - a histone chaperone that binds the retained N-terminus of MLL, co-activates HOXA with it, and is itself a HOXA-activating fusion partner that recruits DOT1L
33. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 37901324
    The outcome of acute leukemia patients with SET-NUP214 fusion after allogeneic stem cell transplantation.

    Shen Y, et al. · Front Oncol 2023
    used by SET::NUP214 adult T-ALL is gamma-delta-lineage-restricted and resistant to steroids and chemotherapy early - the same cell state CALM-AF10 occupies
34. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 37001534
    Defibrotide plus best standard of care compared with best standard of care alone for the prevention of sinusoidal obstruction syndrome (HARMONY): a randomised, multicentre, phase 3 trial.

    Grupp SA, Corbacioglu S, Kang HJ, Teshima T, Khaw SL, Locatelli F, Maertens J, Stelljes M, et al. · The Lancet Haematology 2023
    used by Sinusoidal obstruction syndrome after infant conditioning - an age signal, a regulatory exposure threshold, and a prophylaxis that failed its randomised trial
35. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36662812
    SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia.

    Chambers C, Cermakova K, Chan YS, et al. · Cancer Res 2023
    used by SMARCA4 (BRG1) - a tumour suppressor by mutation and a maintenance requirement by knockdown, and in KMT2A-rearranged lines the dependency data say it is not selective at all
36. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 38065069
    SON is an essential m6A target for hematopoietic stem cell fate.

    Luo H, Cortes-Lopez M, Tam CL, Xiao M, Wakiro I, et al. · Cell Stem Cell 2023
    used by SON (P18583) - a nuclear speckle scaffold that BINDS MENIN and inhibits MLL complex assembly, and the one protein in this tranche the Skucha authors name in their own discussion
37. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36766705
    Taspase1 Facilitates Topoisomerase IIbeta-Mediated DNA Double-Strand Breaks Driving Estrogen-Induced Transcription

    Oelschlager L, Stahl M, Kaschani F, Stauber RH, et al. · Cells 2023
    used by TASP1 (taspase1) - the protease that cuts KMT2A, and the timer the fusion escapes, TOP2A - the proliferation isoform, the one the drugs are actually measured against, and the only one with a germline association in this disease, TOP2B - the isoform most etoposide-induced KMT2A breaks depend on, resolved genetically and not resolvable pharmacologically
38. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35833755
    Mutational landscape and clinical outcome of pediatric acute myeloid leukemia with 11q23/KMT2A rearrangements.

    Yuen KY, Liu Y, et al. · Cancer Med 2023
    used by The comutation confound: KRAS, DNMT3A, TP53 and KMT2A-PTD track with partner and carry prognostic weight of their own
39. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
    CRISPR-ChIP to identify mechanisms of chromatin regulation [RNA-seq] (GSE192561)

    Gilan O, Dawson MA, et al. (GEO submitters) · NCBI Gene Expression Omnibus 2023
    used by The CRISPR-ChIP H3K79 partition is a mouse MLL-AF9 result: resolved from GEO after the full text proved unreachable
40. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 36744954
    The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function.

    Singer MR, Dinh T, et al. · mBio 2023
    used by The HIV field is NOT drugging LEDGF: LEDGINs and ALLINIs bind integrase, and the proof is that they still work in a LEDGF knockout cell
41. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36975603
    Chemical Inhibitors Targeting the Histone Lysine Demethylase Families with Potential for Drug Discovery

    Das ND, ..., Umehara T · Epigenomes 2023
    used by The KDM6 contradiction resolved one step: GSK-J4 inhibits UTX too, so it should ANTAGONISE a menin inhibitor - and nobody has combined them
42. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset
    GEO series GSE192562, GSE192561, GSE192555 and GSE192544 - CRISPR-ChIP to identify mechanisms of chromatin regulation (Series_pubmed_id 37679565)

    · NCBI Gene Expression Omnibus 2023
    used by The menin/H3K79 partition this graph leans on was measured in MURINE MLL-AF9 - resolved from GEO, because the abstract does not say
43. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.preprintPMID 36945621
    Analysis of histone antibody specificity directly in sequencing data using siQ-ChIP.

    Kupai A, Vaughan RM, Rothbart SB, Dickson BM · bioRxiv 2023
    used by The only absolute-scale H3K79me2 deposit this project has contains no IgG or no-primary library, so the 1-31% residual measured after DOT1L inhibition cannot be separated from antibody background - the single cheapest missing control in the dataset
44. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36928776
    UBE2T resolves transcription-replication conflicts and protects common fragile sites in primordial germ cells.

    Yu Y, Xu W, et al. · Cell Mol Life Sci 2023
    used by Transcription–replication conflict as the candidate reason KMT2A-rearranged cells need the Fanconi pathway — a chain with two measured links and three inferred ones
45. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 37720104
    The human leukemic oncogene MLL-AF4 promotes hyperplastic growth of hematopoietic tissues in Drosophila larvae.

    Johannessen JA, Formica M, Haukeland ALC, Bråthen NR, Al Outa A, Aarsund M, Therrien M, Enserink JM, Knævelsrud H · iScience 2023
    used by What this beat read and did not use: bounded absences, bounded rejections and one bounded unreadable
46. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 37609817
    AFF4 globally affects the release of paused RNA polymerase II in HEL cells.

    Yang ZM, Zhang G, Wei G, Jing LL, Yu M · Yi Chuan 2023
    used by What was searched, what came back empty, and what was read and not used - the P-TEFb reservoir beat's audit trail
47. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
    Supplementary Table MOESM3 of PMID 36843114: phosphosite matrix across 74 KMT2A-rearranged AML patients, retrieved via Europe PMC supplementaryFiles

    · EMBL-EBI / Signal Transduction and Targeted Therapy 2023
    used by Which of our phospho-sites are actually seen in patients
48. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36727672
    Exportin 1-mediated nuclear/cytoplasmic trafficking controls drug sensitivity of classical Hodgkin's lymphoma.

    Caillot M, Miloudi H, Taly A, et al. · Molecular Oncology 2023
    used by XPO1 E571K: a change-of-function hot spot in the NES-binding groove - and it does NOT confer resistance to the drugs that bind the same groove
49. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 35245435
    MLL::AF9 degradation induces rapid changes in transcriptional elongation and subsequent loss of an active chromatin landscape.

    Olsen SN, Godfrey L, Healy JP, Choi YA, Kai Y, Hatton C, Perner F, Haarer EL, Nabet B, Yuan GC, Armstrong SA · Molecular Cell 2022
    used by "Menin was lost" and "menin did not move" are both true of the same experiment: a target-gene-restricted signal measure and a genome-wide peak-presence measure answer different questions, and the majority of the genome that does not move is exactly what the second one is made of, A binary peak call cannot see a two-fold change, so 'the peaks are still there' is not 'the protein is still there', A menin inhibitor is not a fusion degron, so watching menin leave chromatin under one cannot identify what was holding it there - every model predicts the same result, Agency law — actual authority, apparent authority, and what revocation cannot undo, At gene resolution the menin inhibitor is the stronger single agent, and only the combination approaches the degron, Attribution audit 1 of 5 - who co-purifies with KMT2A::AFF1: the inventory does not survive, the individual partner blots mostly do, Attribution audit 3 of 5 - where KMT2A::AFF1 sits in the nucleus: the endogenous image does not survive, the overexpression images do and say something different, Attribution audit 4 of 5 - the half-life and turnover of KMT2A::AFF1: this class SURVIVES, and it is the only endogenous fusion-attributable protein measurement this beat found, Attribution audit 5 of 5 - where KMT2A::AFF1 sits on chromatin: the field's standard attribution heuristic is invalidated by the paper that founded it, but two real survivors exist, Bounding an absence the graph already asserts: the H3K79me2 decay half-life, counted, dated and controlled - and why three of the six hits are about the drug's half-life, CDK9 peak widths more than double after fusion degradation, firing the pre-registered re-score trigger, Does the fusion's programme fall apart in the same order in KMT2A::AFF1 as in MLL::AF9? The chain's only ordering measurement, repeated on the index fusion, DOT1L leaves chromatin before menin does when the fusion is degraded, and the ordering survives a change of instrument that destroys the magnitudes - ChIP-qPCR at selected loci, target-restricted read counts and genome-wide peak presence all rank DOT1L ahead of menin while disagreeing about every number, Every published MLL-fusion degron tags an overexpressed construct, not the endogenous allele - and that distinction decides what the washout kinetics mean, Experiment: build the missing KMT2A::AFF1 degron and titrate it — what fractional occupancy does the program actually need?, Experiment: combinatorial dose-titration of the HOXA9/MEIS1 program to find its minimal cut set, Experiment: long-hold degron depletion of endogenous KMT2A::AFF1, to ask whether the leukaemic program recovers without the fusion, Experiment: measure the two missing time constants — how fast the KMT2A::AFF1 program collapses on drug, and how fast it comes back off drug, Experiment: spike-in-calibrated, fusion-attributable occupancy of KMT2A::AFF1 in the first 24 hours of menin inhibition, scored for gains as well as losses, GSE173599 deposits menin ChIP at three hours and nowhere else - no 24 h, no 4 d - so the central question this beat raises, whether menin's persistence is fusion-independence or merely a slow off-rate, cannot be answered from the only degron deposit that exists, and the GEO record advertises four-day menin ChIP that was never deposited, H3K4me3 and wild-type MLL1 are the negative controls for the partition, and both come out flat, How much HOXA9 and MEIS1 is actually required? Partial dependence, a Hox code, and why this caps what any single target can do, Hypothesis: menin-inhibitor effect is hysteretic — the program collapses faster than it recovers — so intermittent dosing can hold efficacy at much lower cumulative exposure, Knock a tag-plus-degron cassette into the endogenous KMT2A::AFF1 allele in SEM - one construct that makes five claim classes attributable, Menin does NOT leave chromatin when the fusion is removed: three hours after MLL::AF9 is degraded to 2.5-7.1% of its own chromatin sites, menin still holds 80.0% of its strongest peak calls genome-wide - so menin occupancy is not a readout of fusion occupancy, and a menin inhibitor that displaces menin is doing something fusion loss does not do, Menin does not outlast the fusion under revumenib in primary infant material - 0.586 against 0.485 at oncoprotein peaks, a ratio of 1.21 against a pre-registered threshold of 1.5 - so the fusion-independent menin plateau seen after a degron does not reproduce here, Menin loses half its promoter signal where the fusion sat, and nothing where it did not, Menin persists on chromatin after the fusion is degraded because LEDGF/PSIP1 supplies a fusion-independent tether - the authors' own proposal, never tested, and the single cheapest experiment that would change how menin displacement is interpreted as a drug readout, Necessary is not explanatory: four different questions that a knockout answers as if they were one, Peak-call retention tracks peak strength, not fusion occupancy, and that inverts the answer, Plain-English: what transcription elongation is, and why a traffic light explains this leukemia, Re-bound at full text: the H3K79me2 decay half-life is still unmeasured - one paper in 12.4 million full texts contains the phrase 'half-life of H3K79me2', it is an unnumbered assertion citing a 2010 review, and the MLL::AF9 degron time-course that could have measured it uses the word zero times, Removing the fusion is a transcription event first and a chromatin event later, and the gap is enormous: nascent transcription changes within 15 minutes, while genome-wide RNA Pol II peak calls are 99.6% retained at 3 hours and not one active histone mark loses a peak call by 24 hours - the fusion's immediate job is licensing elongation, not building a chromatin landscape, Reversibility and kinetics — does the program collapse when the fusion is removed, and how fast?, Scored against the same DMSO in the same batch, degrading the fusion leaves 1.0% of its chromatin sites, the DOT1L+menin combination leaves 10.7%, the menin inhibitor alone leaves 51.7% and the DOT1L inhibitor alone 75.5% - and in a second independent batch the menin inhibitor again beats the DOT1L inhibitor on the fusion's own channel, Step 4 — The histone mark: DOT1L and H3K79me2/3 at fusion target genes (and why global expression barely moves), The 1 kb bin-overlap retention measure this project uses for eviction FAILS a degron positive control: it reports the fusion as still occupying 40-93% of its own sites in cells where the fusion has been destroyed, because a collapsing ChIP signal makes MACS call FEWER but 1.9x WIDER peaks - so it fails hardest exactly where the protein is most completely gone, The active chromatin landscape does not lose a single peak call within 24 hours of the fusion being destroyed: H3K79me2 holds 99.7% at both 3 h and 24 h, H3K9ac 100.0% at both, H3K27ac 83.3%/67.2%, H3K4me3 99.6%/78.9% - while the authors, measuring signal at fusion target genes, report a marked H3K79me2 reduction by 24 h, The DOT1L inhibitor removes menin from fusion promoters too, which a pure interface model does not predict, The experiment nobody has done: an epitope tag knocked into the endogenous KMT2A fusion allele in a patient-derived line, The experiment this deposit is one arm short of: MEN1 ChIP after fusion degradation with a PSIP1-depletion arm, a spike-in, replicates, and timepoints past three hours - four additions to an existing protocol that would settle why menin stays, The five verdicts in one place, plus what this beat read and did not use, The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential, The MLL-side twin of the 1998 anti-AF4 result: in 1997 the same punctate nuclear pattern was seen with and without an 11q23 translocation, and the authors said so, The order in which the fusion's programme collapses is a property of the partner, not of KMT2A - so there is no single causal chain, The positive control this corpus has never had: degrading MLL::AF9 clears its own tag from 93-97% of its strongest chromatin sites within 3 hours, and two INDEPENDENT sequencing batches agree to within 4.6 points - the first technical noise floor ever measured for a ChIP eviction comparison in this project, The specificity control that should have clinched this beat inverts instead: the C-terminal MLL1 epitope the fusion does NOT contain loses MORE than the N-terminal epitope it does contain (68.8% vs 78.4% retained), and because the deposit records different cell-line names for these four samples than for every other one, the arm is reported as uninterpretable rather than interpreted, The stratification passes its own positive control: the fusion tag separates the two strata 62-fold, The working attribution reagent in this literature is not an antibody, it is the gel - and that single fact predicts which claim classes survive, Three hours after the fusion is degraded to 2.5-7.1% of its own sites, NOT ONE of the eight complex components profiled beside it falls below 68% retention genome-wide - menin 80.0%, DOT1L 68.7%, CDK9 83.6%, AFF4 92.7%, RNA Pol II 99.6%, pS2 98.3%, pS5 86.8% - so nothing in the complex is held on chromatin by the fusion at genome scale
50. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 35140242
    Human transcription factor protein interaction networks.

    Göös H, et al. · Nat Commun 2022
    used by A 109-transcription-factor BioID network puts KMT2A next to MYC, YY1 and the ETS and KLF families - and AF10 next to ERG and KLF5, A BioID hit is a neighbour, not a complex member - and the two methods are known to disagree, ELF1 - a direct transcriptional target of MLL fusion proteins and HOXA9 that is ALSO a BioID neighbour of KMT2A, and that is focally deleted in paediatric AML without a KMT2A rearrangement, ELF2 / NERF - an ETS factor that works with RUNX1 on a B-cell kinase promoter, and one of eleven TF baits recovering KMT2A, GATA3 - one of only two transcription-factor baits in a 109-bait BioID screen that recover DOT1L, KMT2A-EN1 declined: one spoke-expanded BioID row from an ectopic neural homeobox construct in a kidney cell, and the only screen that ever looked found EN1 unexpressed in AML lines, NFYC / NF-YC - a histone-fold transcription factor whose partner subunit carries an H2B-like ubiquitination, and the most selective of the eleven TF baits that reached KMT2A, NHLH1 / HEN1 / NSCL1 - a TAL1-family bHLH factor found by cross-hybridising with the T-ALL oncogene, whose knockout mouse is normal and whose only imaging call puts it in the GOLGI, Prey recovery in the two BioID depositions tracks SIZE and not abundance - and the interactome tail was being scored on the wrong side of the pair, because every one of the 22 partners is the BAIT and every core protein is the PREY, TBXT / brachyury - the notochord master regulator, and one of only two of 102 transcription-factor baits whose neighbourhood contained DOT1L, YY1 - the enhancer-promoter looping factor that recovers KMT2A in a 109-transcription-factor BioID screen
51. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
    GSE173599 - Chromatin state changes induced by targeted degradation of MLL-AF9 are phenocopied by combined DOT1L and MENIN inhibition [ChIP-Seq]

    Olsen SN, Hatton C (Armstrong lab, Dana-Farber) · NCBI GEO (SubSeries of GSE173600) 2022
    used by A binary peak call cannot see a two-fold change, so 'the peaks are still there' is not 'the protein is still there', A genome-wide peak-call census is the wrong pharmacodynamic assay for a menin inhibitor, in two independent ways, A GEO deposit can name two different cell lines for the same four samples in two different metadata fields, and reading only the filename - which is what every automated pipeline does - shows you neither: the case where my dispatch brief was right, my correction of it was wrong, and the deposit supports neither of us, A housekeeping normalisation defines the global change to be zero, so only redistribution is measurable, A menin peak that keeps its call has still lost a sixth of its enrichment - and only where the fusion was, CDK9 peak widths more than double after fusion degradation, firing the pre-registered re-score trigger, DOT1L leaves chromatin before menin does when the fusion is degraded, and the ordering survives a change of instrument that destroys the magnitudes - ChIP-qPCR at selected loci, target-restricted read counts and genome-wide peak presence all rank DOT1L ahead of menin while disagreeing about every number, Menin displacement is a poor pharmacodynamic proxy for disabling the fusion, and the degron shows both halves of why: removing the fusion barely moves menin genome-wide, while the menin inhibitor that moves menin leaves half to three-quarters of the fusion's own chromatin sites occupied, Menin does NOT leave chromatin when the fusion is removed: three hours after MLL::AF9 is degraded to 2.5-7.1% of its own chromatin sites, menin still holds 80.0% of its strongest peak calls genome-wide - so menin occupancy is not a readout of fusion occupancy, and a menin inhibitor that displaces menin is doing something fusion loss does not do, Menin persists on chromatin after the fusion is degraded because LEDGF/PSIP1 supplies a fusion-independent tether - the authors' own proposal, never tested, and the single cheapest experiment that would change how menin displacement is interpreted as a drug readout, No HA library exists in the AFF4 sequencing batch, so AFF4 is excluded from the peak partition by name, Peak-call retention tracks peak strength, not fusion occupancy, and that inverts the answer, Re-scored under the measure that passes a degron positive control, cycle 117's MLL1 two-by-two verdict does not merely survive - it strengthens from a 3.33-fold to a 4.64-fold separation between the menin inhibitor and the DOT1L inhibitor, because the MOLM13 arms do not show the peak-broadening that broke the metric elsewhere, Removing the fusion is a transcription event first and a chromatin event later, and the gap is enormous: nascent transcription changes within 15 minutes, while genome-wide RNA Pol II peak calls are 99.6% retained at 3 hours and not one active histone mark loses a peak call by 24 hours - the fusion's immediate job is licensing elongation, not building a chromatin landscape, Scored against the same DMSO in the same batch, degrading the fusion leaves 1.0% of its chromatin sites, the DOT1L+menin combination leaves 10.7%, the menin inhibitor alone leaves 51.7% and the DOT1L inhibitor alone 75.5% - and in a second independent batch the menin inhibitor again beats the DOT1L inhibitor on the fusion's own channel, Spike-in-normalised menin CUT&RUN in a KMT2A::AFF1 degron line, with replicates and a PSIP1 arm, Summit containment passes the positive control that the bin-overlap measure failed, in all three HA batches, The 1 kb bin-overlap retention measure this project uses for eviction FAILS a degron positive control: it reports the fusion as still occupying 40-93% of its own sites in cells where the fusion has been destroyed, because a collapsing ChIP signal makes MACS call FEWER but 1.9x WIDER peaks - so it fails hardest exactly where the protein is most completely gone, The active chromatin landscape does not lose a single peak call within 24 hours of the fusion being destroyed: H3K79me2 holds 99.7% at both 3 h and 24 h, H3K9ac 100.0% at both, H3K27ac 83.3%/67.2%, H3K4me3 99.6%/78.9% - while the authors, measuring signal at fusion target genes, report a marked H3K79me2 reduction by 24 h, The positive control this corpus has never had: degrading MLL::AF9 clears its own tag from 93-97% of its strongest chromatin sites within 3 hours, and two INDEPENDENT sequencing batches agree to within 4.6 points - the first technical noise floor ever measured for a ChIP eviction comparison in this project, The specificity control that should have clinched this beat inverts instead: the C-terminal MLL1 epitope the fusion does NOT contain loses MORE than the N-terminal epitope it does contain (68.8% vs 78.4% retained), and because the deposit records different cell-line names for these four samples than for every other one, the arm is reported as uninterpretable rather than interpreted, The whole deposit is hg38 even where the filename does not say so, and the guard that checked it was worth running, Three hours after the fusion is degraded to 2.5-7.1% of its own sites, NOT ONE of the eight complex components profiled beside it falls below 68% retention genome-wide - menin 80.0%, DOT1L 68.7%, CDK9 83.6%, AFF4 92.7%, RNA Pol II 99.6%, pS2 98.3%, pS5 86.8% - so nothing in the complex is held on chromatin by the fusion at genome scale
52. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset
    GSE173599_TSS_signal_HA_ChIPs.xlsx - per-gene HA (MLL::AF9) TSS signal in four sequencing batches, 19,168 genes each

    Olsen SN et al. · NCBI GEO supplementary file 2022
    used by A genome-wide peak-call census is the wrong pharmacodynamic assay for a menin inhibitor, in two independent ways, Menin loses half its promoter signal where the fusion sat, and nothing where it did not, Summit containment passes the positive control that the bin-overlap measure failed, in all three HA batches, The menin gap survives matching on menin's own signal, but only two deciles of the two strata overlap, The stratification passes its own positive control: the fusion tag separates the two strata 62-fold
53. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35986043
    Biophysical and pharmacokinetic characterization of a small-molecule inhibitor of RUNX1/ETO tetramerization with anti-leukemic effects.

    Gopalswamy M, Kroeger T, Bickel D, Frieg B, Akter S, Schott-Verdugo S, Viegas A, Pauly T, Mayer M, Przibilla J, Reiners J, Nagel-Steger L, Smits SHJ, Groth G, Etzkorn M, Gohlke H · Sci Rep 2022
    used by A genuine small-molecule disruptor of an oncogenic oligomer DOES exist - 7.44 against the RUNX1::RUNX1T1 NHR2 tetramer - which corrects this graph's record; and its eighteen-year potency curve says the class is a chemistry problem, which is what this graph concluded for the wrong reason
54. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset
    GSE173599_TSS_gene_body_signal_Figure3.xlsx - per-gene housekeeping-normalised TSS and gene-body ChIP signal, DMSO vs dTAG-VHL 3 h and 24 h, 16 channels

    Olsen SN et al. · NCBI GEO supplementary file 2022
    used by A housekeeping normalisation defines the global change to be zero, so only redistribution is measurable, A menin peak that keeps its call has still lost a sixth of its enrichment - and only where the fusion was, CDK9 peak widths more than double after fusion degradation, firing the pre-registered re-score trigger, Four days after the fusion is destroyed, menin signal at non-fusion promoters is 27% higher than control, H3K4me3 and wild-type MLL1 are the negative controls for the partition, and both come out flat, Half the menin at fusion-occupied promoters is held by a tether that is not the fusion, Menin loses half its promoter signal where the fusion sat, and nothing where it did not, Menin's departure is partial where the fusion's loss is total, so the two are not stoichiometrically coupled, No HA library exists in the AFF4 sequencing batch, so AFF4 is excluded from the peak partition by name, Spike-in-normalised menin CUT&RUN in a KMT2A::AFF1 degron line, with replicates and a PSIP1 arm, The authors' signal floor removes 92% of non-occupied genes from the menin table, and all of the occupied ones survive, The menin gap survives matching on menin's own signal, but only two deciles of the two strata overlap, The order in which the complex leaves fusion-occupied promoters, all fifteen channels on one scale
55. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset
    GSE173599_TSS_signal_Figure4.xlsx - per-gene HA, DOT1L and MENIN TSS signal after 4 days of EPZ-5676, VTP-50469 or dTAG-VHL (batch 1912x2)

    Olsen SN et al. · NCBI GEO supplementary file 2022
    used by A housekeeping normalisation defines the global change to be zero, so only redistribution is measurable, At gene resolution the menin inhibitor is the stronger single agent, and only the combination approaches the degron, Four days after the fusion is destroyed, menin signal at non-fusion promoters is 27% higher than control, Menin's departure is partial where the fusion's loss is total, so the two are not stoichiometrically coupled, The DOT1L inhibitor removes menin from fusion promoters too, which a pure interface model does not predict, The menin inhibitor removes three-quarters of the fusion from its own promoters, replicated in two batches
56. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35803262
    TK216 targets microtubules in Ewing sarcoma cells.

    Povedano JM, Li V, Lake KE, Bai X, Rallabandi R, Kim J, Xie Y, De Brabander JK, McFadden DG · Cell Chem Biol 2022
    used by A pocketless fusion already had its protein-protein-interface drug taken to phase I/II - and TK216 turned out to be a microtubule destabiliser, not an EWS::FLI1 antagonist. This is the closest thing the field has to a controlled failure of the interface hypothesis.
57. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36136600
    CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.

    · J Clin Invest 2022
    used by A surfaceome-first screen for KMT2A::AFF1: 2,404 surface proteins, 169 expressed in the fusion's own cell lines, 15 fusion-enriched, 3 clean in normal tissue - and the two sets do not intersect, CBFA2T3::GLIS2 supplies its own CAR-T antigen - FOLR1 came out of a list of fusion-specific genes in an isogenic human model. KMT2A-rearranged leukaemia is treated with a LINEAGE antigen it can abandon, or with one a drug has to create; nobody has built the fusion-specific surface list for KMT2A::AFF1., CBFA2T3::GLIS2, inv(16)(p13.3q24.3), Cell-surface capture proteomics on an isogenic human KMT2A::AFF1 model against its matched normal progenitor - the experiment an mRNA screen cannot replace, NUP98::KDM5A (NUP98-JARID1A), t(11;12)(p15;p13)
58. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 36526633
    Detecting and quantifying liquid-liquid phase separation in living cells by model-free calibrated half-bleaching

    Muzzopappa F, et al. · Nature communications 2022
    used by A two-compartment switch for a SEC cargo: nucleolar retention versus AFF4-induced nucleoplasmic droplets, set by one methylated arginine, Condensates in KMT2A-fusion leukemia — an honest verdict: not established for AFF1/AFF4/AF9, load-bearing only in ENL-mutant and NUP98 fusions, Counted absence: AFF1/AF4 - the partner in the commonest infant fusion - has no phase-separation literature under any alias, and the two hits that look like it are token collisions, ELL-EAF1: a phosphorylation-gated interface reported to drive phase separation - and the assays used cannot distinguish that from clustered binding, ENL's disordered region and condensates, restricted to what actually bears on KMT2A::MLLT1 - which is one figure panel, Nothing connects ENL YEATS binding or ENL condensates to phosphorylation: zero records, and what that means for the phase-2 dossier, NUP98 FG condensates, audited assay by assay: no half-bleach has ever been done and no NUP98 fusion has ever been endogenously tagged, The only cellular proposal for how the SEC gets P-TEFb out of the reservoir is a condensate, and the two assays it rests on cannot tell that model from its rival, Where KMT2A::MLLT1 actually sits: chromatin occupancy is mapped, subnuclear localisation of the endogenous fusion has never been imaged
59. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
    PDB entry 7QCR — MLLT4/Afadin PDZ domain in complex with the C-terminal peptide from protein E of SARS-CoV-2, and the UniProt P55196 PDB cross-reference set

    RCSB Protein Data Bank; UniProt Consortium · RCSB Protein Data Bank 2022
    used by AFDN / AF6 — domain architecture and residue coordinates
60. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35468859
    MLL-AF4 and a murinized pSer-variant thereof are turning on the nucleolar stress pathway.

    Siemund AL, Hanewald T, Kowarz E, Marschalek R · Cell Biosci 2022
    used by AFF1 / AF4 — the 3' half of the fusion, and a target with almost no structural footing, GPATCH4 (Q5T3I0) - a nucleolar and Cajal-body helicase cofactor in the pan-MLL-fusion core, with no DHX15 and no G-patch relative beside it, TBL3 / UTP13 (Q12788) - a UTP-B ribosome-biogenesis subunit in the pan-MLL-fusion core, whose loss in zebrafish severely reduces T cells and haematopoietic stem/progenitors, The nucleolus — the one compartment with direct published images of a KMT2A fusion inside it, Three CXXC-pathway activities converge on rDNA - KDM2B represses Pol I, KMT2A and SETD1A bind the whole locus, MLL-AF4 is predominantly nucleolar - and no paper contains two of them
61. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36335100
    RNA-binding proteins of KHDRBS and IGF2BP families control the oncogenic activity of MLL-AF4.

    Okuda H, et al. · Nat Commun 2022
    used by AFF1-RBM15 proximity: the m6A-complex adaptor, itself a paediatric leukaemia fusion partner, has AFF1 in its BioID neighbourhood, KHDRBS1 (Sam68) — an RNA-binding protein that holds the MLL-AF4 message DOWN, a class no dropout screen can find, KHDRBS2 (SLM1) — a counted absence: zero leukaemia records over five aliases, in a family that regulates the MLL-AF4 message, KHDRBS3 (SLM2/T-STAR) — the third STAR paralogue, also zero leukaemia records, also flat in DepMap, RNA-binding proteins set how much KMT2A::AFF1 protein a cell makes from its own fusion transcript, The RNA layer scored for KMT2A-selectivity across 79 genes, lineage-split — PTBP1 is the only menin-shaped hit, and the IGF2BP family shows no co-dependency
62. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35585237
    Gibbin mesodermal regulation patterns epithelial development.

    Collier A, Liu A, Torkelson J et al · Nature 2022
    used by AHDC1 (Gibbin) - an AT-hook chromatin-architecture factor that is already a cofactor of a DIFFERENT sarcoma fusion oncoprotein, and whose KMT2A breakpoint lands in an untranslated exon
63. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36194562
    AT-hook DNA-binding motif-containing protein one knockdown downregulates EWS-FLI1 transcriptional activity in Ewing's sarcoma cells.

    Kitagawa T, Kobayashi D, Baron B et al · PLoS One 2022
    used by AHDC1 (Gibbin) - an AT-hook chromatin-architecture factor that is already a cofactor of a DIFFERENT sarcoma fusion oncoprotein, and whose KMT2A breakpoint lands in an untranslated exon
64. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35476984
    Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells.

    Morris V, Wang D, Li Z, ..., Rowe RG · Cell Rep 2022
    used by AK_7_3, a KMT2A::AFF1-derived fusion circRNA that holds down mitochondrial respiration and ROS in t(4;11) B-ALL - the only mitochondrial mechanism in this beat measured in the index fusion, Cell state in KMT2A-rearranged leukaemia is organised by lineage, not by the fusion — five independent axes split the same way, and every one of them splits AML from ALL rather than partner from partner, Complex I inhibition triggers the mitochondrial integrated stress response through DELE1 and HRI, and that is what creates the MCL-1 dependency - a metabolic drug manufacturing an apoptotic vulnerability, Is the metabolic phenotype a consequence of the fusion programme or an independent dependency? The answer is that BOTH directions are published, and one of them points the other way entirely, Mitochondrial complex I plus venetoclax in KMT2A-rearranged paediatric AML - a genotype-stratified in vivo PDX result, on a drug whose adult clinical development stopped for toxicity, The experiment that separates lineage from ontogeny: one KMT2A fusion, two cell-of-origin contexts, three metabolic perturbations, and a limiting-dilution readout alongside the viability one, The hypoxic, glycolytic state — the one state that appears independently in leukaemia-initiating cells, in measurable residual disease, and in KMT2A-rearranged B-ALL as a class, The myeloid/lymphoid metabolic split in KMT2A-rearranged leukaemia is set by CELL OF ORIGIN (fetal versus adult), not by lineage or by the fusion partner, The OXPHOS-dependent state — established in KMT2A-rearranged AML, and inverted in KMT2A-rearranged B-ALL where OXPHOS inhibition makes leukaemia-initiating cells appear
65. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 35512704
    Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.

    Mo X, Niu Q, Ivanov AA, Tsang YH, Tang C, Shu C, Li Q, Qian K, Wahafu A, Doyle SP, Cicka D, Yang X, Fan D, Reyna MA, Cooper LAD, Moreno CS, Zhou W, Owonikoko TK, Lonial S, Khuri FR, Du Y, Ramalingam SS, Mills GB, Fu H · Cell 2022
    used by All nine unwritten MEN1 partners trace to exactly two publications, neither of which mentions menin outside an antibody catalogue row, MEN1-AKT1 is ONE BRET well from a mutation screen, for the E17K allele only - declined, MEN1-BRAF V600E: four methods and an endogenous menin lane - the only one of the nine that is a real observation, and it is still a property of the allele, MEN1-EGFR is ONE BRET well from the extended-driver arm of a mutation screen, for L858R only - declined, MEN1-FBXW7 is four alleles of ONE BRET assay, all typed 'mutation with no effect' - declined, and it is the most insidious class, MEN1-PTEN is ONE BRET well from the extended-driver arm, for R173C only - declined, MEN1-SMAD4 is four alleles of ONE BRET assay, all 'mutation with no effect' - declined, and the real menin-TGF-beta literature is elsewhere, MEN1-SPOP is four alleles of ONE BRET assay, all 'mutation with no effect' - declined, with a nuclear-speckle confound, Menin's 33 curated partners, enumerated: 10 written, 10 discarded as mutation-directed or single-method, 3 that are not proteins, and what was read and rejected, SMARCA4 (BRG1) - a tumour suppressor by mutation and a maintenance requirement by knockdown, and in KMT2A-rearranged lines the dependency data say it is not selective at all, Ten of menin's 33 IntAct partners come from one BRET screen for MUTATION-created interactions — and five are gains caused by a named allele
66. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.datasetPMID 35868306
    Integrative analysis of drug response and clinical outcome in acute myeloid leukemia

    Bottomly D, Long N, Schultz AR, et al. · Cancer Cell 40:850-864.e9 2022
    used by All three pre-registered branches came out of the same numbers under four defensible floors - the expressed/silent binary was measuring the ruler, not the gene
67. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35839448
    Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia

    Tirtakusuma R, Szoltysek K, Milne P, et al. · Blood 2022
    used by Analysis (runnable): build a methylome cell-of-origin score for infant KMT2A-rearranged ALL and test it as a predictor of lineage destination, CHD4 (Q14839) - the NuRD ATPase, a pan-MLL-fusion co-purifier, and the gene whose disruption drives lineage switching in KMT2A::AFF1 relapse, Competitive release and adaptive therapy — what ecology says happens when you remove the dominant species, Experiment: go back to the diagnostic sample and look for the myeloid clone before it existed, Hypothesis: the myeloid clone that appears after CD19-directed therapy was already there at diagnosis, and its abundance is a pre-treatment biomarker, Hypothesis: where a blast goes when the fusion program is released is written in its methylome at diagnosis, not in its transcriptome, Lineage switch in KMT2A-rearranged leukemia — the same clone changes what kind of blood cell it is, Myeloid-primed blasts are already present at diagnosis of KMT2A-rearranged B-ALL and expand under immunotherapy — the single-cell demonstration this graph recorded as not existing, Pentimento and restoration — the fusion overpaints the cell, and cleaning reveals whatever was underneath, The second ring — smaller KMT2A-fusion mechanism labs, and where the literature actually points
68. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35022500
    Differential roles of BAF and PBAF subunits, Arid1b and Arid2, in MLL-AF9 leukemogenesis

    Bluemn T, ... Zhu N · Leukemia 2022
    used by Analysis: cross-validating the single-group non-menin KMT2A-fusion dependencies in one framework, ARID1A (BAF250A) - required in the MLL-AF9 screen, present at the Myc enhancers, and flat in every selectivity measure, ARID1B (BAF250b) - the cBAF paralogue whose deletion PROMOTES MLL-AF9 leukaemogenesis, which makes it the one gene in this beat whose published KMT2A-fusion result points the wrong way for a drug target, ARID2 (BAF200) - the PBAF subunit whose loss ACCELERATES MLL-AF9 leukaemia, and which is nonetheless required to maintain it, The second ring — smaller KMT2A-fusion mechanism labs, and where the literature actually points
69. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36042201
    Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia

    Isobe T, Takagi M, Sato-Otsubo A, Nishimura A, Nagae G, Yamagishi C, Tamura M, Tanaka Y, Asada S, Takeda R, Tsuchiya A, Wang X, Yoshida K, Nannya Y, Ueno H, Akazawa R, Kato I, Mikami T, Watanabe K, Sekiguchi M, Seki M, Kimura S, Hiwatari M, Kato M, Fukuda S, Tatsuno K, Tsutsumi S, Kanai A, Inaba T, Shiozawa Y, Shiraishi Y, Chiba K, Tanaka H, Kotecha RS, Cruickshank MN, Ishikawa F, Morio T, Eguchi M, Deguchi T, Kiyokawa N, Arakawa Y, Koh K, Aoki Y, Ishihara T, Tomizawa D, Miyamura T, Ishii E, Mizutani S, Wilson NK, Gottgens B, Miyano S, Kitamura T, Goyama S, Yokoyama A, Aburatani H, Ogawa S, Takita J · Nature Communications 2022
    used by Analysis: score fetal, myeloid-priming and differentiation-stage signatures across public KMT2A-r datasets, Enumeration for the partner-outcome beat: what was searched, what was used, what was rejected, what could not be read, Experiment: is the primed state in KMT2A::AFF1 actually bivalent? Multi-mark CUT&Tag on primary infant blasts, Experiment: where do KMT2A::AFF1 blasts go when a menin inhibitor releases the block? Single-cell lineage destination under drug, Fusion partner predicts the molecular subgroup almost perfectly, and survival not at all, KRAS - the commonest co-mutation in a disease that has almost none, and it is usually in a minority of the cells, Multipotent progenitor (MPP) — the stage where the undifferentiated KMT2A-r infant leukaemias map, The differentiation block — what it actually is, operationally, in KMT2A::AFF1 leukaemia, The early lymphocyte precursor (ELP) state — what KMT2A-rearranged infant B-ALL scores as against a developing bone marrow reference, and why it is earlier than the pro-B arrest this graph also records, The primed chromatin state — what is actually established, and why the word 'bivalent' should be used carefully here
70. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35014621
    Menin Enhances Androgen Receptor-Independent Proliferation and Migration of Prostate Cancer Cells.

    Kim T, et al. · Mol Cells 2022
    used by AR / androgen receptor - the best-supported partner in the absence set by independent-publication count, and the reason a menin inhibitor is in prostate cancer trials
71. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36184659
    Histone chaperone ASF1A accelerates chronic myeloid leukemia blast crisis by activating Notch signaling.

    Yin X, Zhou M, Zhang L, et al. · Cell Death & Disease 2022
    used by ASF1A - the compensating paralogue: the only gene in this beat that is not required in a single one of 1,208 cell lines, and it still has a leukaemia phenotype
72. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36513698
    Loss of the Ash2l subunit of histone H3K4 methyltransferase complexes reduces chromatin accessibility at promoters.

    Barsoum M, Stenzel AT, Bochyńska A, et al. · Sci Rep 2022
    used by ASH2L: the only WRAD subunit ever perturbed in a KMT2A::AFF1 cell, once, weakly
73. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset
    GSE173599_TSS_signal_Figure5.xlsx - per-gene HA and H3K27ac TSS signal after 4 days of EPZ-5676, VTP-50469, the combination or dTAG-VHL (batch 200908)

    Olsen SN et al. · NCBI GEO supplementary file 2022
    used by At gene resolution the menin inhibitor is the stronger single agent, and only the combination approaches the degron, The menin inhibitor removes three-quarters of the fusion from its own promoters, replicated in two batches
74. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36305813
    ATM-mediated ELL phosphorylation enhances its self-association through increased EAF1 interaction and inhibits global transcription during genotoxic stress.

    Pal S, et al. · Nucleic Acids Res 2022
    used by ATM - the DNA-damage kinase that phosphorylates three of the four KMT2A 3' partners, ATM phosphorylates ELL at T551, S561 and S589 - inside the OCEL domain this graph already calls essential for MLL-ELL immortalisation, Induction chemotherapy phospho-inactivates KMT2A fusions through PIKK sites the partner retains - and a DNA-PK or ATM inhibitor would block that
75. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35612819
    Design, Synthesis, and Biological Evaluations of DOT1L Peptide Mimetics Targeting the Protein-Protein Interactions between DOT1L and MLL-AF9/MLL-ENL.

    Yuan Y, Du L, Tan R, et al. · J Med Chem 2022
    used by Blocking where DOT1L binds instead of what it does - the modality that removes the mark only at fusion targets
76. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35650206
    Nuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis.

    · Nat Commun 2022
    used by BMI1 - the self-renewal gene that KMT2A fusions can do without, because HOXA9 covers for it at the same locus
77. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
    Dot1L recruits OGT target chromatin to regulate histones O-GlcNAcylation (GSE200059)

    GEO submitters · NCBI Gene Expression Omnibus 2022
    used by Bounded failure with a near-miss worth recording: a GEO series matching the topic exactly belongs to a different paper
78. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.news
    Syndax Announces U.S. FDA Breakthrough Therapy Designation Granted for Revumenib for the Treatment of Adult and Pediatric Patients with Relapsed or Refractory KMT2A-Rearranged (MLLr) Acute Leukemia

    Syndax Pharmaceuticals, Inc. · PR Newswire 2022
    used by Breakthrough therapy and accelerated approval: the menin field took the fast review and declined the shortcut
79. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34054042
    Management of Hyperleukocytosis in Childhood Acute Leukemia Without Leukapheresis and Rasburicase Prophylaxis.

    Aylan Gelen S, Sarper N, Zengin E, et al. · Journal of Pediatric Hematology/Oncology 2022
    used by Bruising and petechiae: the bleeding signs of thrombocytopenia at presentation, Hyperleukocytosis: why a very high white-cell count is a medical emergency, Pallor and fatigue: the anaemia of a marrow taken over by leukaemia
80. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34255148
    Analysis of risk factors for hepatic sinusoidal obstruction syndrome following allogeneic hematopoietic stem cell transplantation in pediatric patients.

    Kloehn J, Brodt G, Ernst J, Gruhn B · Journal of Cancer Research and Clinical Oncology 2022
    used by Busulfan - the alkylating agent that replaces radiation in infant conditioning, and whose labelled paediatric target range is below the range the modern trial data support, Sinusoidal obstruction syndrome after infant conditioning - an age signal, a regulatory exposure threshold, and a prophylaxis that failed its randomised trial
81. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.journal-articlePMID 34582559
    The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML.

    Heikamp EB, Henrich JA, Perner F, et al. · Blood 2022
    used by CALM-AF10 was meant to separate the menin axis from the HOXA programme - and the indirect evidence has now turned against separability, because KMT2A-free HOXA lesions keep proving menin-DEPENDENT, Evicting the fusion is not enough: PRC1.1 has to arrive, and losing it causes menin-inhibitor resistance in vivo, Eviction is a claim about menin. The field, and this graph, transfer it to the fusion without a measurement that supports the transfer, Experiment: endogenously tagged KMT2A::AFF1 imaged through a menin-inhibitor time course, with a five-compartment segmentation and a half-life arm, Hypothesis: menin inhibition does not merely displace KMT2A::AFF1 from chromatin, it destabilises it — the evicted fusion is degraded, not parked, Import class 5: evidence borrowed from fusions that are not KMT2A fusions at all, In NUP98-rearranged leukaemia, who responds to a menin inhibitor is decided by the co-mutations, not by the fusion, Menin dependency tracks the availability of an intact menin-binding motif, in cis or in trans — not the fusion family, MOF/KAT8 is required by both KMT2A::MLLT3 and NUP98::HOXA9 — which is why it is the wrong kind of convergence, NUP98 fusions share the menin dependency (confirmed preclinically) — and the partner-supplied reader/writer module is not why, NUP98::HOXA9, t(7;11)(p15;p15) — the founding NUP98 fusion, and an incomplete oncogene, NUP98::HOXD13, t(2;11)(q31;p15) — the myelodysplasia fusion, and a warning against targeting p53, NUP98::KDM5A (NUP98-JARID1A), t(11;12)(p15;p13), NUP98::NSD1 without FLT3-ITD loses its prognostic significance — the confound that undermines the fusion's own reputation, SAVE (NCT05360160): the first prospective menin-inhibitor trial to report a NUP98-rearranged subgroup outcome, The nuclear pore and NUP98 fusions — a fusion that takes a pore protein's disordered repeats off the pore and builds nuclear droplets with them, The pivotal menin-inhibitor paper reports that the drug does NOT globally displace MLL1 or the fusion from chromatin - menin goes, the fusion largely stays, Two constructs that would decide whether menin dependency is about the menin-binding motif or about HOXA level, Two hypotheses in this graph make the same prediction on every lesion that exists, and the experiment queued to test them picks the one arm where neither speaks, What could refute the menin-interface bet, restated after the provenance audit: three tests, none of which is about menin binding, Where does the fusion go when menin inhibition evicts it? Almost nobody has looked - the published readouts are chromatin occupancy, the one protein whose fate was measured properly is menin, and the single human observation of fusion loss is confounded by a lineage switch, Why a nucleoporin fusion needs menin-MLL1: the second menin-dependent fusion family, and what it borrows rather than carries
82. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 35618797
    The bone marrow niche regulates redox and energy balance in MLL::AF9 leukemia stem cells

    Vinado AC, Calvo IA, Cenzano I, Olaverri D, Cocera M, San Martin-Uriz P, et al. · Leukemia 2022
    used by CAR cell (CXCL12-abundant reticular) / LEPR+ perivascular stromal cell — the cell that makes the signal holding blood stem cells in the marrow, CXCL12 (SDF-1) - the marrow retention chemokine this graph already had a mechanism entry for and no entry for the protein, CXCL12-CXCR4 retention — the axis everyone calls the niche dependency, and the CRISPR screen that says the ligand is not required, Experiment: give an antioxidant with the CXCR4 antagonist — if the drug stops working, the niche is a redox buffer and not a hiding place, Osteoblast — the bone-building niche cell whose expansion suppresses CML and makes MLL-AF9 AML worse, The unnamed osteolineage Cre is Prx1-Cre, which is not osteoblast-restricted - and that changes what the negative result means
83. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 35797463
    Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN.

    Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, Ebert BL, Fenaux P, Godley LA, Hasserjian RP, Larson RA, Levine RL, Miyazaki Y, Niederwieser D, Ossenkoppele G, Röllig C, Sierra J, Stein EM, Tallman MS, Tien HF, Wang J, Wierzbowska A, Löwenberg B · Blood 2022
    used by CBFA2T3::GLIS2, inv(16)(p13.3q24.3)
84. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35013097
    CCND3 is indispensable for the maintenance of B-cell acute lymphoblastic leukemia

    Ketzer F, Abdelrasoul H, Vogel M, Marienfeld R, Muschen M, Jumaa H, Wirth T, Ushmorov A · Oncogenesis 11:1 2022
    used by CCND3 (cyclin D3) — the scan's rank-4 hit, and the only one of the four with a drug class already in children, CDK4/6 inhibition in KMT2A-rearranged leukemia — the class was already tried, and the trial never reported, CDK6 - the kinase the KMT2A-r rationale actually rests on, and the pan-essentiality flag and the selectivity are both true
85. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36084658
    Tisagenlecleucel therapy for relapsed or refractory B-cell acute lymphoblastic leukaemia in infants and children younger than 3 years of age at screening: an international, multicentre, retrospective cohort study

    Ghorashian S, Jacoby E, De Moerloose B, et al. · Lancet Haematology 2022
    used by CD19 CAR-T in infants with KMT2A-rearranged ALL — it works, it is manufacturable, and it does not hold, Haematopoietic stem cell transplant in KMT2A-rearranged infant leukemia — what it is for, and why most children who need it never get it, MRD as a trial endpoint in KMT2A-rearranged leukaemia: high negativity rates, and almost none of them say which assay
86. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35421218
    CD34+CD19-CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies.

    Bueno C, ..., Menendez P · Blood 2022
    used by CD22 (SIGLEC2) - the antigen that comes on BEFORE CD19, which makes it both the backup target and the pre-loaded escape route, CD34 - named in 132 entries of this graph and written in none, and it does not mean what the graph has been using it to mean
87. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 35007127
    Phase II Trial of Inotuzumab Ozogamicin in Children and Adolescents With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: Children's Oncology Group Protocol AALL1621.

    O'Brien MM, ..., Loh ML · J Clin Oncol 2022
    used by CD22 (SIGLEC2) - the antigen that comes on BEFORE CD19, which makes it both the backup target and the pre-loaded escape route
88. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33526373
    Precursor B-lineage acute lymphoblastic leukemia patients with aberrant natural killer cell and T cell - lineage antigen expression: experience from a tertiary cancer care center.

    Bommannan K, ..., Sundersingh S · Hematol Transfus Cell Ther 2022
    used by CD7 - the T/NK antigen on a B blast that flags KMT2A rearrangement and worse event-free survival, and the fourth antigen on the lineage-switch list
89. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35017466
    Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

    Fiskus W, Boettcher S, Daver N, Mill CP, Sasaki K, Birdwell CE, Davis JA, Takahashi K, Kadia TM, DiNardo CD, et al. · Blood Cancer Journal 12:5 2022
    used by CDK6 - the kinase the KMT2A-r rationale actually rests on, and the pan-essentiality flag and the selectivity are both true, The CRM1 address is not a menin-free address: NPM1c reaches HOXA the same way and NPM1c AML is menin-inhibitor-sensitive in the clinic
90. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36220893
    Nucleus-translocated mitochondrial cytochrome c liberates nucleophosmin-sequestered ARF tumor suppressor by changing nucleolar liquid-liquid phase separation.

    González-Arzola K, et al. · Nat Struct Mol Biol 2022;29:1024-1036 2022
    used by CDKN2A - one gene, two reviewed UniProt records with the same primary symbol, and a deletion that is three times rarer here than in the infant leukaemias next door
91. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35158754
    High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia

    Liu L, Patnana PK, Xie X, Frank D, Nimmagadda SC, Rosemann A, et al., Khandanpour C · Cancers (Basel) 2022
    used by Cell state in KMT2A-rearranged leukaemia is organised by lineage, not by the fusion — five independent axes split the same way, and every one of them splits AML from ALL rather than partner from partner, Is the metabolic phenotype a consequence of the fusion programme or an independent dependency? The answer is that BOTH directions are published, and one of them points the other way entirely, The myeloid/lymphoid metabolic split in KMT2A-rearranged leukaemia is set by CELL OF ORIGIN (fetal versus adult), not by lineage or by the fusion partner, The OXPHOS-dependent state — established in KMT2A-rearranged AML, and inverted in KMT2A-rearranged B-ALL where OXPHOS inhibition makes leukaemia-initiating cells appear
92. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33910331
    LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for mixed lineage leukemia-rearranged acute leukemia.

    · Haematologica 2022
    used by Cell-surface capture proteomics on an isogenic human KMT2A::AFF1 model against its matched normal progenitor - the experiment an mRNA screen cannot replace, LAMP5 (BAD-LAMP) - a direct MLL-fusion target gene, a proposed immunotherapy antigen, and a brain protein, LAMP5 was proposed as an immunotherapy target for MLL-rearranged leukaemia without a normal-tissue filter; two atlases independently put it above 290 in the basal ganglia, and it is not partner-specific either, LAMP5-directed therapy for KMT2A-rearranged leukaemia would meet the basal ganglia, in a disease treated in infants and routinely treated into the CNS, REFUTED IN THE CYCLE IT WAS WRITTEN - the proposal that fusion-driven and normal-tissue-clean surface antigens are disjoint in KMT2A::AFF1 because of what the fusion's output programme is; an expression-matched permutation says it is the base rate, The innate-immune-rewired state — LAMP-5 is a direct fusion target that routes signalling away from interferon and toward NF-kB, and the cell depends on that routing, The interferon state is not baseline in this disease — it is something a menin inhibitor creates, through endogenous retrovirus induction and MHC class II, The screen this beat was dispatched to run 'because it has never been run' was published in Haematologica in 2022, used the same instrument, and is cited in this graph already - in an entry filed under innate immunity
93. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35534777
    IKAROS and MENIN coordinate therapeutically actionable leukemogenic gene expression in MLL-r acute myeloid leukemia.

    Aubrey BJ, Cutler JA, Bourgeois W, et al. · Nat Cancer 2022
    used by Census of every published chromatin-occupancy measurement made under a menin inhibitor: eight datasets, every one TSS-anchored, every one tabulating losses only
94. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34551064
    Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML.

    Menghrajani K, Gomez-Arteaga A, et al. · Blood Adv 2022
    used by CIBMTR post-transplant AML (n=426 KMT2A-r, curated cytogenetics): no outcome difference by fusion partner
95. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35799191
    First-in-human phase I study of CLL-1 CAR-T cells in adults with relapsed/refractory acute myeloid leukemia.

    Jin X, Zhang M, Sun R, Lyu H, Xiao X, Zhang X, et al. · J Hematol Oncol 2022
    used by CLEC12A (CD371, CLL-1, MICL) - the leukaemic-stem-cell antigen whose therapeutic rationale rests on an absence, and which menin inhibition appears to induce, Q48 enumeration: every antigen, identifier and query this beat ran - including what was searched and rejected, and the three identifier traps found live, Risk: CLEC12A-directed therapy ablates normal granulocytes and disables an inhibitory brake on NET formation - the toxicity is mature-myeloid, not stem-cell
96. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36272410
    Hotspot mutations in the structured ENL YEATS domain link aberrant transcriptional condensates and cancer

    Song L, Yao X, Li H, et al. (Wan L, senior author) · Molecular Cell 82(21):4080-4098.e12 2022
    used by Condensates in KMT2A-fusion leukemia — an honest verdict: not established for AFF1/AFF4/AF9, load-bearing only in ENL-mutant and NUP98 fusions, ELL-EAF1: a phosphorylation-gated interface reported to drive phase separation - and the assays used cannot distinguish that from clustered binding, ENL's disordered region and condensates, restricted to what actually bears on KMT2A::MLLT1 - which is one figure panel, ENL's nuclear annotation has no citation at all, and every picture of ENL in a nucleus is of a mutant or a fusion, never the wild-type protein, Experiment: does KMT2A::AFF1 form condensates at endogenous levels, and does it need them? The separation-of-function and IDR-swap test, Hypothesis: KMT2A::AFF1 does not require phase separation — recruitment biochemistry is sufficient, and the condensate model does not transfer from NUP98/ENL, Nothing connects ENL YEATS binding or ENL condensates to phosphorylation: zero records, and what that means for the phase-2 dossier, Transcription factories and Pol II clusters - no KMT2A::AFF1 imaging, condensate evidence for SEC and MLL-ENL, and 3D-FISH that actively contradicts the factory story for t(4;11), Where KMT2A::MLLT1 actually sits: chromatin occupancy is mapped, subnuclear localisation of the endogenous fusion has never been imaged
97. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34903620
    Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation

    Chandra B, Michmerhuizen NL, Shirnekhi HK, et al. (Kriwacki RW, senior author) · Cancer Discovery 12(4):1152-1169 2022
    used by Condensates in KMT2A-fusion leukemia — an honest verdict: not established for AFF1/AFF4/AF9, load-bearing only in ENL-mutant and NUP98 fusions, Experiment: does KMT2A::AFF1 form condensates at endogenous levels, and does it need them? The separation-of-function and IDR-swap test, NUP98 FG condensates, audited assay by assay: no half-bleach has ever been done and no NUP98 fusion has ever been endogenously tagged
98. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35073946
    SMARCA5 interacts with NUP98-NSD1 oncofusion protein and sustains hematopoietic cells transformation.

    Jevtic Z, Matafora V, Casagrande F, et al. (Schwaller J, Bachi A, senior authors) · Journal of Experimental & Clinical Cancer Research 41(1):34 2022
    used by Condensates in KMT2A-fusion leukemia — an honest verdict: not established for AFF1/AFF4/AF9, load-bearing only in ENL-mutant and NUP98 fusions, The nuclear pore and NUP98 fusions — a fusion that takes a pore protein's disordered repeats off the pore and builds nuclear droplets with them
99. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36713383
    CK2beta-regulated signaling controls B cell differentiation and function.

    Quotti Tubi L, Mandato E, Canovas Nunes S, Arjomand A, Zaffino F, et al. · Front Immunol 2022
    used by CSNK2B / CK2beta (P67870) - the regulatory subunit of casein kinase 2, in the pan-MLL-fusion core, with no CSNK2B-and-KMT2A literature at all
100. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35180428
     HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia

     Luo H, Zhu G, Eshelman MA, Fung TK, Lai Q, Wang F, Zeisig BB, Lesperance J, Ma X, Chen S, Cesari N, Cogle C, Chen B, Xu B, Yang FC, So CWE, Qiu Y, Xu M, Huang S · Molecular Cell 2022
     used by CTCF/cohesin boundaries and the HOXA topological domain — the 3D scaffold the fusion program runs on, HOTTIP lncRNA — the 5' HOXA switch that holds the leukemic chromatin domain open, Hypothesis: the R-loop landscape of a KMT2A::AFF1 blast is remodelled by the fusion and is both a vulnerability and a source of ongoing genome instability, Transcription–replication conflict as the candidate reason KMT2A-rearranged cells need the Fanconi pathway — a chain with two measured links and three inferred ones
101. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34852272
     Crystal Structure of the Core Module of the Yeast Paf1 Complex.

     · J Mol Biol 2022
     used by CTR9 — a PAF1C subunit the field assumes is a fusion partner, with no paper that tested it
102. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34999734
     Fast H3K9 methylation promoted by CXCL12 contributes to nuclear changes and invasiveness of T-acute lymphoblastic leukemia cells

     · Oncogene 2022
     used by CXCL12 (SDF-1) - the marrow retention chemokine this graph already had a mechanism entry for and no entry for the protein
103. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35390758
     Idax and Rinf facilitate expression of Tet enzymes to promote neural and suppress trophectodermal programs during differentiation of embryonic stem cells.

     Abou-Jaoude A, Huang CY, et al. · Stem Cell Res 2022
     used by CXXC4 (IDAX) - TET2's CXXC domain, sitting on a separate gene after an evolutionary inversion, and annotated cytoplasmic only by similarity
104. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34304246
     Identification and characterization of relapse-initiating cells in MLL-rearranged infant ALL by single-cell transcriptomics

     Candelli T, Schneider P, Garrido Castro P, Jones LA, Bodewes E, Rockx-Brouwer D, et al., Stam RW · Leukemia 2022
     used by Diagnosis versus relapse in the same child: relapse comes from a subclone that was already there and already quiescent, shown twice, seven years apart, by two unrelated methods, The corpus citation index reads `PMID nnnnnnnn` in prose and never the `pmid` citation field — it sees 1,908 of 3,991 papers, undercounts 872 of the rest, and its headline single-cell absence was an artefact, The relapse-initiating persister state — present at diagnosis, identifiable before a single dose is given, and defined by basal glucocorticoid-response activation plus small size plus quiescence, Use centrifugal elutriation, not a chemical block: the one separation method demonstrated to work in KMT2A-rearranged cells, applied to both the cell-cycle question and the small-persister question
105. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35145224
     Elucidating minimal residual disease of paediatric B-cell acute lymphoblastic leukaemia by single-cell analysis

     Zhang Y, Wang S, Zhang J, Liu C, Li X, Guo W, et al., Cheng T · Nat Cell Biol 2022
     used by Diagnosis versus relapse in the same child: relapse comes from a subclone that was already there and already quiescent, shown twice, seven years apart, by two unrelated methods, The hypoxic, glycolytic state — the one state that appears independently in leukaemia-initiating cells, in measurable residual disease, and in KMT2A-rearranged B-ALL as a class, The relapse-initiating persister state — present at diagnosis, identifiable before a single dose is given, and defined by basal glucocorticoid-response activation plus small size plus quiescence
106. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35970937
     A structure-based mechanism for displacement of the HEXIM adapter from 7SK small nuclear RNA.

     Pham VV, Gao M, Meagher JL, Smith JL, D'Souza VM · Commun Biol 2022
     used by Directed extraction of P-TEFb from the reservoir: HIV-1 Tat is the worked example, and the only cellular candidate rests on one unreplicated paper, How P-TEFb gets out of the reservoir: a dephosphorylation, a dissociation, and a reassembly on whichever scaffold is waiting, RN7SK / 7SK snRNA - the 332-nucleotide brake on elongation, and the one molecule in this beat that every dataset this project uses is blind to
107. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35739357
     H2B Lys34 Ubiquitination Induces Nucleosome Distortion to Stimulate Dot1L Activity.

     Ai H, Sun M, Liu A, Sun Z, Liu T, Cao L, Liang L, Qu Q, Li Z, Deng Z, Tong Z, Chu G, Tian X, Deng H, Zhao S, et al. · Nat Chem Biol 2022
     used by Does the fusion carry an H2B ubiquitin ligase? A co-IP and an H2BK34ub CUT&RUN in KMT2A::AFF1 cells, H2BK34ub — a second ubiquitination site on H2B that also stimulates DOT1L, written by MSL1/MSL2, and important at HOXA9 and MEIS1, MSL2 — the second H2B ubiquitin ligase, sitting inside the MOF complex the KMT2A fragment contacts, The fusion may reach the H2B ubiquitin mark through MOF-MSL rather than through RNF20/RNF40 — the one configuration in which this layer could be selective
108. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 36095189
     Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome.

     Rahman S, Hoffmann NA, Worden EJ, et al. · Proc Natl Acad Sci U S A 2022
     used by DPY30: the founding negative does not cover it, and it has no KMT2A contact to lose, WDR5 and RBBP5: the second arm of the WRAD hub, RBBP5 V375-D376-V377 into the same propeller face, co-crystallised with the MLL1 WIN peptide in one structure
109. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35082269
     Clinico-biological features of T-cell acute lymphoblastic leukemia with fusion proteins

     Steimle T, Dourthe ME, Alcantara M, Touzart A, Simonin M, Mondesir J, et al., Asnafi V · Blood Cancer Journal 2022
     used by Early T-cell precursor (ETP) — the thymocyte that has not yet given up being myeloid, and where KMT2A-rearranged T-ALL sits
110. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36037515
     Prolonged XPO1 inhibition is essential for optimal antileukemic activity in NPM1-mutated AML.

     Pianigiani G, Gagliardi A, Mezzasoma F, et al. · Blood Advances 2022
     used by Eltanexor (KPT-8602) - the second-generation SINE whose whole point is that you can give it more often, NPM1c and XPO1: one drug, one output, two incompatible mechanisms - is the mutant needed in the cytoplasm or on the chromatin?, Two reasons XPO1 is a hard target: every cell needs it, and blocking it switches on a survival pathway, XPO1 mRNA goes UP when you inhibit the protein - the pharmacodynamic marker that made the paediatric trial interpretable, and what it cannot tell you
111. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.databasePMID 34751401
     ReMap 2022: a database of Human, Mouse, Drosophila and Arabidopsis regulatory regions from an integrative analysis of DNA-binding sequencing experiments.

     Hammal F, de Langen P, Bergon A, et al. · Nucleic Acids Research 2022
     used by ENCODE spells zero as HTTP 404, ReMap spells it as HTTP 401, and GEO spells it as a well-formed count of zero under a retired symbol - three archives, three spellings, and two of them are indistinguishable from a broken connection
112. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
     A Phase 1/2, Open-Label, Dose-Escalation, Dose-Expansion Study of Enzomenib (DSP-5336) in Patients With Acute Leukemia and Other Selected Hematologic Malignancies (Horizen-1)

     Sumitomo Pharma America, Inc. · ClinicalTrials.gov 2022
     used by Enzomenib (DSP-5336) — menin inhibitor with the highest reported KMT2A-r response rate and little differentiation syndrome, No menin-inhibitor or DOT1L-inhibitor trial has ever named this fusion - and the DOT1L trials excluded it by construction, Sumitomo Pharma — enzomenib (DSP-5336): one trial, adolescents at 12 years and 40 kg, no paediatric programme
113. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35247902
     ZNF384 Fusion Oncoproteins Drive Lineage Aberrancy in Acute Leukemia.

     Dickerson KM, Qu C, Gao Q, Iacobucci I, Gu Z, Yoshihara H, Backhaus EA, Chang Y, Janke LJ, Xu B, Wu G, Papachristou EK, D'Santos CS, Roberts KG, Mullighan CG · Blood Cancer Discov 2022
     used by EP300::ZNF384 - the commonest ZNF384 fusion, and it throws away the acetyltransferase, Express a partner-free ZNF384 C-terminal truncation in HSPCs alongside TCF3::ZNF384 - the one experiment that decides whether the fusion partner is necessary, FLT3 in ZNF384-rearranged leukaemia - the fusion builds its own enhancer 25 kb upstream, and gilteritinib works in xenografts, Four sources give ZNF384 three different zinc-finger counts - 8, 6 and 'five to eight' - and the paralogue's feature table explains where the 6 comes from, How common is ZNF384-rearranged leukaemia? Published answers span 1.6% to about 20% and the spread is almost entirely denominator, not biology, Last-exon indels that truncate the ZNF384 C-terminus phenocopy the fusion - so the fusion partner may not be the necessary element, TCF3::ZNF384 - the partner whose contribution is now actually demonstrated: steroid resistance, and it is not shared with EP300::ZNF384, ZNF384 fusions make lineage-ambiguous leukaemia by acting in a haematopoietic stem cell - and the founding lesion is in the HSC itself, unlike Ph-like B-ALL
114. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34936860
     Potent macrocycle inhibitors of the human SAGA deubiquitinating module.

     Morgan M, Ikenoue T, Suga H, Wolberger C · Cell Chem Biol 2022
     used by Erasing H2Bub: three deubiquitinases share two adaptors, and removing the enzyme the field names lowers the mark instead of raising it, Nobody knows which way to push H2Bub in this disease, and the only available compound pushes it upward, Raise H2Bub in KMT2A-rearranged cells with the existing USP22 macrocycles and see which way the disease moves, USP22 — a KMT2A-rearranged dependency that works through MEIS1 protein stability, and is not an interactor of the fusion
115. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35483357
     Tuning levels of low-complexity domain interactions to modulate endogenous oncogenic transcription

     Chong S, Graham TGW, Dugast-Darzacq C, Dailey GM, Darzacq X, Tjian R · Molecular Cell 2022
     used by EWSR1::FLI1 — the comparator that shows condensate formation has an optimum, and that forcing a fusion into the nucleolus switches it off, EWSR1::FLI1 (EWS-FLI1), t(11;22)(q24;q12), The case that the KMT2A-fusion condensate is an artefact — what 1,6-hexanediol, overexpressed tags and in-vitro droplets actually prove
116. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36444977
     Fixation can change the appearance of phase separation in living cells

     Irgen-Gioro S, Yoshida S, Walling V, Chong S · eLife 2022
     used by Experiment: endogenously tagged KMT2A::AFF1 imaged through a menin-inhibitor time course, with a five-compartment segmentation and a half-life arm, The case that the KMT2A-fusion condensate is an artefact — what 1,6-hexanediol, overexpressed tags and in-vitro droplets actually prove
117. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36104354
     Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia.

     Zhao X, et al. · Nat Commun 2022
     used by Express a partner-free ZNF384 C-terminal truncation in HSPCs alongside TCF3::ZNF384 - the one experiment that decides whether the fusion partner is necessary, FLT3 in ZNF384-rearranged leukaemia - the fusion builds its own enhancer 25 kb upstream, and gilteritinib works in xenografts, The ZNF384 family is not the inverse of KMT2A::AFF1 - it is the SAME grammar written in the opposite gene order, and three of the four claims in the inverse framing are false
118. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35443564
     Persistent DNA damage and oncogenic stress-induced Trem1 promotes leukemia in mice.

     Li X, Chatla S, et al. · Haematologica 2022
     used by FANCA — FA core complex; rank 20 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
119. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35644338
     FANCL supports Parkin-mediated mitophagy in a ubiquitin ligase-independent manner.

     Beesetti S, et al. · Biochim Biophys Acta Mol Basis Dis 2022;1868:166453 2022
     used by FANCL — FA core complex; rank 26 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
120. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34871373
     Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy

     Leahy AB, Devine KJ, Li Y, Liu H, Myers R, DiNofia A, et al. · Blood 139(14):2173-2185 2022
     used by FLT3 in KMT2A-r leukemia — near-universal overexpression, but activating mutation in only ~3% of infants, Lineage switch as antigen escape from CD19-directed therapy in KMT2A-rearranged leukemia, The near-silent genome of infant KMT2A-r ALL — 1.3 non-silent mutations, and why that is bad news as well as good
121. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     GEO Series GSE185093 — Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia [ChIP-Seq]

     Wan L, Liu Y, Li H, Li Q · NCBI Gene Expression Omnibus 2022
     used by Four YEATS antagonists exist, four public transcriptome datasets of YEATS inhibition exist, and not one paper or dataset has ever asked what happens to the AFF2- or AFF3-scaffolded complexes — and the analysis needs no wet work
122. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 36053276
     Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia.

     Liu Y, Li Q, Alikarami F, Barrett DR, Mahdavi L, Li H, Tang S, Khan TA, Michino M, Hill C, Song L, Yang L, Li Y, Pokharel SP, Stamford AW, Liverton N, Renzetti LM, Taylor S, Watt GF, Ladduwahetty T, Kargman S, Meinke PT, Foley MA, Shi J, Li H, Carroll M, Chen CW, Gardini A, Maillard I, Huggins DJ, Bernt KM, Wan L · Cancer Discovery 2022
     used by Four YEATS antagonists exist, four public transcriptome datasets of YEATS inhibition exist, and not one paper or dataset has ever asked what happens to the AFF2- or AFF3-scaffolded complexes — and the analysis needs no wet work, SGC-iMLLT - the MLLT1/MLLT3 YEATS chemical probe, and the 2026 paper that put it into KMT2A::AFF1 in vivo with a healthy-HSPC comparison, Which step is rate-limiting, and what compensates when you block it — the bite-back map for the causal chain
123. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36171271
     HMG20B stabilizes association of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block

     Maiques-Diaz A, Nicosia L, Basma NJ, Romero-Camarero I, Camera F, Spencer GJ, Amaral FMR, Simeoni F, Wingelhofer B, Williamson AJK, Pierce A, Whetton AD, Somervaille TCP · Oncogene 41:4841-4854 2022
     used by GFI1 — the repressor that LSD1 inhibitors actually work through, and the scan hit whose literature points the opposite way, The LSD1–GFI1 SNAG interface — a second worked example of drugging an undruggable repressor through its partner
124. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36003783
     Presence of the GFI1-36N single nucleotide polymorphism enhances the response of MLL-AF9 leukemic cells to CDK4/6 inhibition

     Vorwerk J, Sun K, Frank D, Neumann F, Huve J, Budde PM, Liu L, Xie X, Patnana PK, Ahmed HMM, Opalka B, Lenz G, Jayavelu AK, Khandanpour C · Frontiers in Oncology 12:903691 2022
     used by GFI1 — the repressor that LSD1 inhibitors actually work through, and the scan hit whose literature points the opposite way
125. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     GSE173599 supplementary file list and series record (!Series_overall_design), retrieved and parsed 2026-09-23

     Olsen SN, Armstrong SA, et al. · NCBI Gene Expression Omnibus 2022
     used by GSE173599 deposits menin ChIP at three hours and nowhere else - no 24 h, no 4 d - so the central question this beat raises, whether menin's persistence is fusion-independence or merely a slow off-rate, cannot be answered from the only degron deposit that exists, and the GEO record advertises four-day menin ChIP that was never deposited, The experiment this deposit is one arm short of: MEN1 ChIP after fusion degradation with a PSIP1-depletion arm, a spike-in, replicates, and timepoints past three hours - four additions to an existing protocol that would settle why menin stays
126. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36332031
     USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3.

     Sijm A, Atlasi Y, van der Knaap JA, Wolf van der Meer J, Chalkley GE, Bezstarosti K, et al. · Sci Adv 2022
     used by H2AK119ub - the mark every PRC1.1 claim in this graph rests on, named in fifteen entries and written in none until now, In inv(16), disrupting the fusion interface swaps BRG1 for RING1B at three MYC enhancers - the cleanest version anywhere of the experiment nobody has run on menin, USP7 - the enzyme that holds PRC1.1 together, and the only pharmacological handle on this complex that exists today
127. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset
     GSE173599_ChIPseq_TSS_Figure3_revisions.xlsx - per-gene MLL1 N-terminal and C-terminal TSS signal, DMSO vs dTAG-VHL 3 h, plus the 21-gene housekeeping normalisation panel and the published MLL::AF9 target-gene lists

     Olsen SN et al. · NCBI GEO supplementary file 2022
     used by H3K4me3 and wild-type MLL1 are the negative controls for the partition, and both come out flat, Half the menin at fusion-occupied promoters is held by a tether that is not the fusion, Menin loses half its promoter signal where the fusion sat, and nothing where it did not, The authors' signal floor removes 92% of non-occupied genes from the menin table, and all of the occupied ones survive, The menin gap survives matching on menin's own signal, but only two deciles of the two strata overlap, The order in which the complex leaves fusion-occupied promoters, all fifteen channels on one scale, The stratification passes its own positive control: the fusion tag separates the two strata 62-fold
128. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36139405
     Bioinformatic Analyses of Broad H3K79me2 Domains in Different Leukemia Cell Line Data Sets.

     Sharma P, Sattarifard H, Fatemiyan N, et al. · Cells 2022
     used by H3K79me2 - the di-methyl state the leukaemia actually runs on, and the one menin turns out to govern only half of, HOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it
129. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35434944
     HSF1 facilitates the multistep process of lymphatic metastasis in bladder cancer via a novel PRMT5-WDR5-dependent transcriptional program.

     Huang M, Dong W, Xie R, Wu J, et al. · Cancer Commun (Lond) 2022
     used by H3R2me2s - the symmetric mark on the SAME residue as H3R2me2a, which permits rather than enhances WRAD access, and whose 'enhancing' half this graph inherited from the paper that was later revised
130. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35668193
     P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.

     Lin KH, Rutter JC, Xie A, et al. · Nature Cancer 2022
     used by Has anyone tested an XPO1 inhibitor in a KMT2A-rearranged system? Yes - four preclinical studies and zero clinical ones, counted with the queries and the controls, Two reasons XPO1 is a hard target: every cell needs it, and blocking it switches on a survival pathway
131. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35906225
     CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors.

     Lloyd SM, Leon DB, Brady MO, Rodriguez D, McReynolds MP, Kweon J, Neely AE, Blumensaadt LA, Ho PJ, Bao X · Nat Commun 2022
     used by HEXIM1 - the brake pad, the only part of the reservoir anyone has deliberately raised in a KMT2A-rearranged cell, and the result was that the leukaemia grew less, P-TEFb phosphorylates AFF4 and rearranges the complex the fusion hijacks
132. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34961794
     Histone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability.

     Guo P, Liu Y, Geng F, et al. · Nature Cell Biology 2022
     used by HIRA - the chaperone that puts new H3.3 into transcribed gene bodies, and therefore the machine that runs this graph's clearance clock, Histone H3.3 - one protein, two genes, and the reason this graph should not file it as gene-h3f3a
133. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35409391
     Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy.

     Semchenkova A, Mikhailova E, Komkov A, Gaskova M, Abasov R, Matveev E, et al., Zerkalenkova E, Popov A · Int J Mol Sci 2022
     used by How common is ZNF384-rearranged leukaemia? Published answers span 1.6% to about 20% and the spread is almost entirely denominator, not biology, Lineage switch to myeloid leukaemia under CD19-directed therapy in ZNF384-rearranged ALL - and in the one cohort that caught both families, the ZNF384 switch looked mutationally NOTHING like the KMT2A ones
134. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34935961
     Disrupting the Cdk9/Cyclin T1 heterodimer of 7SK snRNP for the Brd4 and AFF1/4 guided reconstitution of active P-TEFb.

     Zhou K, Zhuang S, Liu F, Chen Y, Li Y, Wang S, Li Y, Wen H, Lin X, Wang J, Huang Y, He C, et al · Nucleic Acids Res 2022
     used by How P-TEFb gets out of the reservoir: a dephosphorylation, a dissociation, and a reassembly on whichever scaffold is waiting, P-TEFb phosphorylates AFF4 and rearranges the complex the fusion hijacks
135. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.journal-articlePMID 35171113
     Loss of MEN1 function impairs DNA repair capability of pancreatic neuroendocrine tumors.

     Lakiza O, Lutze J, Vogle A, et al. · Endocr Relat Cancer 2022
     used by HR genes are menin-bound at 1.76x and so is ribosome biogenesis at 1.78x: the pathway-specific reading does not survive its own control, The menin-inhibitor plus PARP-inhibitor experiment is genuinely unrun, but its rationale should be DNA repair, not HOXA9 - and the evidence comes from a disease where menin is a tumour suppressor
136. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.datasetPMID 34864916
     Single-cell multiomics reveals increased plasticity, resistant populations, and stem-cell-like blasts in KMT2A-rearranged leukemia — Data Availability Statement

     Chen C, Yu W, Alikarami F, et al. (senior author Tan K) · Blood 2022
     used by HTAN KMT2A-r ALL single-cell multiome — 25 patients (18 infants), scRNA-seq + scATAC-seq + snmC-seq2, with 2 paired pre/post lineage-switch cases and analysis code on GitHub, Hypothesis: the myeloid clone that appears after CD19-directed therapy was already there at diagnosis, and its abundance is a pre-treatment biomarker, Myeloid-primed blasts are already present at diagnosis of KMT2A-rearranged B-ALL and expand under immunotherapy — the single-cell demonstration this graph recorded as not existing, Score the HSPC-like fraction on paired pre-treatment and on-treatment samples from KMT2A-rearranged patients receiving a menin inhibitor — a flow-first design with a single-cell confirmatory arm, The HSPC-like blast fraction — a minority of blasts that transcriptionally resemble haematopoietic stem and progenitor cells, found in the blood of the youngest KMT2A-rearranged patients and predicting drug response and outcome across leukaemia subtypes, The HSPC-like blast fraction is the compartment that survives menin inhibition, and its size at diagnosis predicts depth and durability of response
137. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 35455547
     Leukapheresis in Pediatric Acute Leukemia with Hyperleukocytosis: A Single-Center Experience

     Jones SR, et al. · Children (Basel) 2022
     used by Hyperleukocytosis: why a very high white-cell count is a medical emergency
138. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34321607
     The RNA-binding protein IGF2BP3 is critical for MLL-AF4-mediated leukemogenesis

     Tran TM, et al. · Leukemia 2022
     used by Hypothesis: IGF2BP2 and IGF2BP3 buffer each other in KMT2A::AFF1 leukaemia, so single-gene CRISPR under-reports both, I3IN-002 — the first small-molecule IGF2BP3 inhibitor with in vivo activity in an MLL-Af4 model, IGF2BP3 — an RNA-binding protein required for MLL-Af4 leukaemogenesis in mice that CRISPR barely touches in human lines, RNA-binding proteins set how much KMT2A::AFF1 protein a cell makes from its own fusion transcript, The decisive experiment: acute degron removal of IGF2BP3, IGF2BP2 and both, read on self-renewal and xenograft initiation rather than bulk dropout, We have read a tenth of the recent field, and the gap found a real interactor
139. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35379703
     Mllt11 Regulates Migration and Neurite Outgrowth of Cortical Projection Neurons during Development.

     Stanton-Turcotte D, Hsu K, Moore SA, Yamada M, Fawcett JP, Iulianella A · J Neurosci 2022
     used by Hypothesis: tubulin/microtubule association is a recurrent, unnamed property of the KMT2A partners whose transforming module has no other assignment, MLLT11 / AF1q — a 90-residue protein with no chromatin domain and no oligomerisation module, KMT2A partner in t(1;11)(q21;q23)
140. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 36233173
     Normal and Aberrant TALE-Class Homeobox Gene Activities in Pro-B-Cells and B-Cell Precursor Acute Lymphoblastic Leukemia

     Nagel S, Meyer C · Int J Mol Sci 2022
     used by iALL-IRX1 — the HOXA-negative, IRX1-high state of infant KMT2A::AFF1 ALL, IRX1 — Iroquois homeobox 1, the gene that names the HOXA-negative half of infant t(4;11) ALL, IRX1 is reported as expressed in AML subsets, so its absence from oncoprotein occupancy outside KMT2A::AFF1 is not an absence of IRX1, IRX2 - the IRX-cluster neighbour that is this disease's own prognostic gene, activated only in KMT2A::AFF1, and never written here until now, Is IRX1 expressed in normal blood at all? Two of the three papers say no, one says exclusively yes, Verdict: q147's IRX1 headline survives as a measurement and not as an inference - the pre-registered branch is NEITHER, on U5 and on a FALLS condition that fired
141. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35800767
     The immune checkpoint ICOSLG is a relapse-predicting biomarker and therapeutic target in infant t(4;11) acute lymphoblastic leukemia.

     Kulp M, Siemund AL, Larghero P, Dietz A, Alten J, Cario G, et al. · iScience 2022
     used by ICOSLG on infant t(4;11) blasts converts T cells into regulatory T cells - the one immune-evasion route measured in this exact disease, in this exact age group, Which immune-evasion routes are actually documented in KMT2A-rearranged disease, and which are borrowed from AML and assumed - a ranked ledger with the bounded absences that define it
142. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36306790
     The m(6)A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia

     Weng H, et al. · Cancer Cell 2022
     used by IGF2BP2 — the paralogue co-over-expressed with IGF2BP3 in MLL/AF4 B-ALL, and the one with an inhibitor in another leukaemia
143. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35915142
     Inhibition of the m(6)A reader IGF2BP2 as a strategy against T-cell acute lymphoblastic leukemia

     Feng P, et al. · Leukemia 2022
     used by IGF2BP2 — the paralogue co-over-expressed with IGF2BP3 in MLL/AF4 B-ALL, and the one with an inhibitor in another leukaemia
144. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35525905
     Discovery of a dual WDR5 and Ikaros PROTAC degrader as an anti-cancer therapeutic.

     Li D, Yu X, Kottur J, Gong W, et al. · Oncogene 2022
     used by IKZF3 / Aiolos (Q9UKT9) - the B-lymphoid transcription factor that goes UP under both inhibitors, regulates BCL2, and is a degradable drug target
145. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34855461
     CD123 Expression Is Associated With High-Risk Disease Characteristics in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group.

     Lamble AJ, ..., Meshinchi S · J Clin Oncol 2022
     used by IL3RA / CD123 - not just a myeloid target: the quartile of CD123 expression that carries the KMT2A rearrangements is the quartile that dies, Myeloid-directed antigens (CD33, CD123) — the only immunotherapy axis that survives lineage switch
146. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35328612
     The Hematopoietic TALE-Code Shows Normal Activity of IRX1 in Myeloid Progenitors and Reveals Ectopic Expression of IRX3 and IRX5 in Acute Myeloid Leukemia

     Nagel S, Pommerenke C, Meyer C, MacLeod RAF · Int J Mol Sci 23:3192 2022
     used by IRX1 expression in KMT2A-rearranged paediatric AML is a FAB-M7 megakaryoblastic property, not a fusion property: 13 of 20 M7 versus 2 of 96 M5, and non-KMT2A-r M7 is 54 of 97, IRX1 is reported as expressed in AML subsets, so its absence from oncoprotein occupancy outside KMT2A::AFF1 is not an absence of IRX1, IRX1 status is set by the cell of origin, and the fusion partner predicts it only because different partners transform different cells - so the partner supplies no IRX1 address, IRX2 - the IRX-cluster neighbour that is this disease's own prognostic gene, activated only in KMT2A::AFF1, and never written here until now
147. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35884588
     Conjoined Genes as Common Events in Childhood Acute Lymphoblastic Leukemia

     Severgnini M, D'Angio M, Bungaro S, Cazzaniga G, Cifola I, Fazio G · Cancers (Basel) 2022
     used by Is fusion intended in biology sometimes? Yes, and the answer has a strategic edge, Newborn screening for leukaemia fusions: verdict NOT FEASIBLE TODAY, and the reason is arithmetic plus the absence of anything to offer a positive, Read-through (cis-SAGe) chimeras: most 'fusions' called from RNA-seq in childhood ALL are normal conjoined genes
148. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35256780
     Loss of IRF7 accelerates acute myeloid leukemia progression and induces VCAM1-VLA-4 mediated intracerebral invasion

     · Oncogene 2022
     used by ITGA4 (CD49d, the alpha-4 of VLA-4) - the niche adhesion subunit with an approved antibody and a 2026 KMT2A-r B-ALL xenograft result, VCAM1 - the stromal counter-receptor for VLA-4, and in MLL-fusion AML its UPREGULATION is anti-leukaemic, which is the opposite of the expected sign
149. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33361104
     Adult phenotype in Koolen-de Vries/KANSL1 haploinsufficiency syndrome

     Amenta S, Frangella S, Marangi G, Lattante S, Ricciardi S, Doronzio PN, Orteschi D, Veredice C · Journal of Medical Genetics 59:189-195 2022
     used by KANSL1 - the NSL scaffold, and the protein through which WDR5 binding to NSL and to MLL/COMPASS is mutually exclusive
150. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35945623
     Single-cell diploid Hi-C reveals the role of spatial aggregations in complex rearrangements and KMT2A fusions in leukemia

     Xing Z, Mai H, Liu X, et al. (senior author Wen F) · Genome Biology 2022
     used by KMT2A and several of its fusion partners occupy the same spatial cluster in individual nuclei before any break occurs — single-cell diploid Hi-C, RUNX1-dependent, and 3D architecture does NOT predict which fusion type a cell will make
151. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 35271311
     OpenCell: Endogenous tagging for the cartography of human cellular organization.

     Cho NH, Cheveralls KC, Brunner AD, Kim K, Michaelis AC, Raghavan P, Kobayashi H, Savy L, et al. (27 authors), Leonetti MD · Science 2022
     used by KMT2A-HMGN5: recovered by endogenous CRISPR tagging in OpenCell, not by over-expression - a chromatin-decompacting nucleosome binder with a real reason to be near KMT2A, NUMA1 / NuMA (Q14980) - a nuclear-matrix protein that becomes the spindle pole, and the 5' partner of a variant APL fusion whose coiled-coil is required for oncogenicity
152. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 35091795
     A rare case of acute megakaryoblastic leukemia with t(11;17)(q23;q21) and KMT2A::MLLT6 fusion.

     Qiu L, Nunez CA, Tang G, Cuglievan B, Issa GC, Wang SA, et al. · Ann Hematol 2022
     used by KMT2A::MLLT6 (MLL-AF17), t(11;17)(q23;q12-q21) — the bridge case: a leucine zipper on a DOT1L-complex subunit
153. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35734412
     Novel Diagnostic and Therapeutic Options for KMT2A-Rearranged Acute Leukemias.

     Lopes BA, Poubel CP, Teixeira CE, Caye-Eude A, Cavé H, Meyer C, Marschalek R, Boroni M, Emerenciano M · Frontiers in Pharmacology 2022
     used by KMT2A::USP2, inv(11)(q23.3q23.3) - the minor-BCR fusion that keeps the PHD fingers, USP2 (ubiquitin carboxyl-terminal hydrolase 2) - the ninth commonest KMT2A partner and the only one that is a deubiquitinase
154. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36204688
     Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood KMT2A-rearranged Acute Leukemia.

     Pilheden M, Ahlgren L, Hyrenius-Wittsten A, et al. · HemaSphere 2022
     used by KRAS - the commonest co-mutation in a disease that has almost none, and it is usually in a minority of the cells, Measure the RAS allele fraction in CSF blasts and in paired marrow blasts from the same infant on the same day, NRAS - the other RAS, the one whose 0.3% clone came back, and a UniProt record that lists HRAS1 as its own synonym, PAX5 - the most frequently hit non-KMT2A gene in infant KMT2A-rearranged ALL, and it is a deletion in one allele, not a mutation, PIK3R1 in KMT2A-rearranged infant ALL - the only cooperating lesion in this disease that was functionally proved to be activating, and it is an ITD, PTPN11/SHP2 - non-recurrent in infant KMT2A-rearranged ALL, well drugged everywhere else, and the one leukaemia trial that carried a SHP2 inhibitor was withdrawn, Subclonal cooperating lesions lost at relapse - what was actually measured, and why 'lost' is the wrong word, The quiet genome, audited - the famous 1.3 mutations is a count of point mutations in the dominant clone, and all three of those words do work, Track the sub-1% cooperating-lesion clones through menin inhibition, because nobody has measured what the drug selects for, Treating a subclonal lesion is selection pressure applied to the clone you did not aim at
155. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33795806
     LEDGF/p75-mediated chemoresistance of mixed-lineage leukemia involves cell survival pathways and super enhancer activators.

     Canella A, Van Belle S, et al. · Cancer Gene Ther 2022
     used by LEDGF as a survival factor rather than a tether: it is upregulated in chemoresistant AML blasts, protects against daunorubicin, and knocking it down sensitises MLLr lines, The LEDGF hole, measured: every published LEDGF-removal experiment removes it BEFORE or AT transformation, and none treats an established leukaemia in an animal
156. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35470240
     Map7D2 and Map7D1 facilitate microtubule stabilization through distinct mechanisms in neuronal cells.

     Kikuchi K, Sakamoto Y, Uezu A, Yamamoto H, Ishiguro KI, Shimamura K, Saito T, Hisanaga SI, Nakanishi H · Life Sci Alliance 2022
     used by MAP7D1 (Q3KQU3) - the strongest index-fusion p-value of the nine deferred pan-MLL-fusion preys, on a protein UniProt places entirely outside the nucleus
157. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35709470
     Optochemical Control of TET Dioxygenases Enables Kinetic Insights into the Domain-Dependent Interplay of TET1 and MBD1 while Oxidizing and Reading 5-Methylcytosine.

     Lin TC, Palei S, et al. · ACS Chem Biol 2022
     used by MBD1 - one protein with a methyl-CpG reader and three CXXC fingers, only the third of which binds unmethylated CpG, and whose CXXC fails the MLL-AF9 swap
158. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36411286
     Regulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability

     Wray JP, Deltcheva EM, Boiers C, Richardson SE, Chhetri JB, Brown J, Gagrica S, Guo Y, Illendula A, Martens JHA, Stunnenberg HG, Bushweller JH, Nimmo R, Enver T · Nature Communications 2022
     used by Mechanism class 2 — transcription-factor corruption (RUNX1::RUNX1T1, PML::RARA, ETV6::RUNX1, CBFB::MYH11) — a balance, not a pure dominant negative
159. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35301220
     A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia.

     Harada T, et al. · Genes Dev 2022;36:368-389 2022
     used by MEF2C — an output-program transcription factor, the second-strongest leukemia co-dependency, and a gene humans cannot spare one copy of
160. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.review
     Multiple Endocrine Neoplasia Type 1 (GeneReviews)

     Giusti F, Marini F, Brandi ML · GeneReviews, University of Washington 2022
     used by MEN1 / menin — the adaptor the fusion cannot work without
161. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 35682627
     Molecular Classification and Overcoming Therapy Resistance for Acute Myeloid Leukemia with Adverse Genetic Factors.

     Ikeda D, et al. · Int J Mol Sci 2022
     used by Menin has never been tested against SET::NUP214 - a bounded absence in three independent registers: literature, cell-line dependency data, and the founding paper's own blots
162. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35954231
     Modeling MEN1 with Patient-Origin iPSCs Reveals GLP-1R Mediated Hypersecretion of Insulin.

     Cheng Z, Guo D, Ruzi A, Pan T, You K, Chen Y, et al. · Cells 2022
     used by Menin represses GLP1R - the receptor a whole class of diabetes drugs exists to switch on
163. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 35732831
     The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms

     Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, et al. · Leukemia 2022
     used by Mixed-phenotype acute leukemia and KMT2A rearrangement — plasticity caught in the act
164. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35650277
     Measurable residual disease analysis in paediatric acute lymphoblastic leukaemia patients with ABL-class fusions.

     Venn NC, Huang L, Hovorková L, et al. · Br J Cancer 2022
     used by MRD by genomic breakpoint: the only assay in this disease that is fusion-specific by construction
165. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34785111
     Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol.

     Stutterheim J, de Lorenzo P, van der Sluis IM, et al. · Eur J Cancer 2022
     used by MRD by Ig/TCR rearrangement: the standard in ALL, and the assay infant KMT2A-rearranged disease strains hardest, Retrospective paired-target MRD on stored Interfant marrows, stratified by IGHV usage
166. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 35489058
     NASP maintains histone H3-H4 homeostasis through two distinct H3 binding modes.

     Bao H, Carraro M, Flury V, et al. · Nucleic Acids Research 2022
     used by NASP - the soluble histone reservoir, and the only gene in this beat with a real selective difference at a pan-essentiality shallow enough to interpret
167. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35177641
     Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice.

     Li T, Lu D, Yao C, Li T, Dong H, Li Z, Xu G, Chen J, Zhang H, Yi X, Zhu H, Liu G, Wen K, Zhao H, Gao J, Zhang Y, Han Q, Li T, Zhang W, Zhao J, Li T, Bai Z, Song M, He X, Zhou T, Xia Q, Li A, Pan X · Nat Commun 2022
     used by Neuron - the off-target cell type that defines what KANSL1 loss costs a human being
168. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36224177
     The coilin N-terminus mediates multivalent interactions between coilin and Nopp140 to form and maintain Cajal bodies.

     Courchaine E, Gelles-Watnick S, Machyna M, Straube K, Sauyet S, et al. · Nat Commun 2022
     used by NOLC1 / Nopp140 (Q14978) - a nucleolar and Cajal-body phosphoprotein in the pan-MLL-fusion core, and the first physical bridge to this graph's nucleolar convergence
169. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36161484
     Human NOP2/NSUN1 regulates ribosome biogenesis through non-catalytic complex formation with box C/D snoRNPs.

     Liao H, Gaur A, McConie H, Shekar A, Wang K, Chang JT, Breton G, Denicourt C · Nucleic Acids Res 2022
     used by NOP2 / NSUN1 / p120 (P46087) - the 28S rRNA m5C4447 methyltransferase in the MLL-fusion nucleolar block, present in the index fusion's column at p = 0.0223, and the gene whose PubMed token is two-thirds contaminated by its NSUN paralogues
170. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 36351646
     [Acute myeloid leukemia harboring NUP98::DDX10]

     Kurita N, et al. · Rinsho Ketsueki 63(10):1397-1401 2022
     used by NUP98::DDX10, inv(11)(p15q22) — the 'helicase' fusion whose helicase activity turns out not to be the point
171. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 34897646
     Two novel cases of NUTM1-rearranged B-cell acute lymphoblastic leukaemia presenting with high-risk features

     McClure BJ, Pal M, Heatley SL, et al. · British Journal of Haematology 2022
     used by NUTM1-rearranged B-ALL - the KMT2A-wild-type arm of the same infant trials, with 4-year EFS of 100% against 36-37% next door
172. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     EU/3/21/2569 - orphan designation for treatment of acute myeloid leukaemia

     European Medicines Agency · EMA orphan designation register 2022
     used by Orphan drug designation: what it actually gives a KMT2A programme, and what it bends, The EU paediatric investigation plan: an obligation, not an incentive - and the deferral is the loophole
173. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35677155
     The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression.

     Xiao L, Karsa M, Ronca E, Bongers A, Kosciolek A, El-Ayoubi A, et al. · Frontiers in Oncology 12:863329 2022
     used by Panobinostat - the HDAC inhibitor this graph has reasoned about for cycles without having an entry for, with strong KMT2A-rearranged xenograft activity and a terminated adult trial
174. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 36552756
     PICALM and Alzheimer's Disease: An Update and Perspectives.

     Ando K, et al. · Cells 2022
     used by PICALM (CALM) - the clathrin-assembly adaptor that is the 5' partner of CALM::AF10
175. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35508169
     Loss of PRMT7 reprograms glycine metabolism to selectively eradicate leukemia stem cells in CML.

     Liu C, Zou W, Nie D, Li S, et al. · Cell Metab 2022
     used by PRMT7 - the enzyme whose class is still disputed, which represses a KMT2 enzyme by writing H4R3me2s, which is required for leukaemia stem cells in CML, and whose only H3R2 claim is the one this beat was dispatched to check
176. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35565298
     Arginine Methyltransferase PRMT7 Deregulates Expression of RUNX1 Target Genes in T-Cell Acute Lymphoblastic Leukemia.

     Oksa L, Mäkinen A, Nikkilä A, Hyvärinen N, et al. · Cancers (Basel) 2022
     used by PRMT7 - the enzyme whose class is still disputed, which represses a KMT2 enzyme by writing H4R3me2s, which is required for leukaemia stem cells in CML, and whose only H3R2 claim is the one this beat was dispatched to check
177. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
     A Phase 1b/2 Master Protocol of Agents Targeting the Mitogen-Activated Protein Kinase Pathway in Patients With Hematologic Malignancies

     Erasca, Inc. · ClinicalTrials.gov 2022
     used by PTPN11/SHP2 - non-recurrent in infant KMT2A-rearranged ALL, well drugged everywhere else, and the one leukaemia trial that carried a SHP2 inhibitor was withdrawn
178. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34767674
     Dysregulation of RalA signaling through dual regulatory mechanisms exerts its oncogenic functions in hepatocellular carcinoma.

     Tian L, Zhao L, Sze KM et al · Hepatology 2022
     used by RALGAPA2 (AS250) - the catalytic brake on RalA that behaves as a tumour suppressor, fused to KMT2A exon 22 in an osteosarcoma and predicted out of frame, which makes allele DISRUPTION the better hypothesis than a chimera
179. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35416979
     RBBP4 dysfunction reshapes the genomic landscape of H3K27 methylation and acetylation and disrupts gene expression.

     Mu W, Murcia NS, Smith KN, Menon DU, Yee D, Magnuson T · G3 (Bethesda) 2022
     used by RBBP4 - the shared histone-binding subunit that every leukaemia line needs, and whose identical-length paralogue cannot replace it
180. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34709113
     Overlapping functions of RBBP4 and RBBP7 in regulating cell proliferation and histone H3.3 deposition during mouse preimplantation development.

     Xiao L, Dang Y, Hu B, Luo L, Zhao P, Wang S, et al. · Epigenetics 2022
     used by RBBP4 - the shared histone-binding subunit that every leukaemia line needs, and whose identical-length paralogue cannot replace it, RBBP7 - the silent paralogue that is not silent, and the reason this project's paralogue rule finally produced a positive answer
181. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36110547
     Anti-Osteoclast Effect of Exportin-1 Inhibitor Eltanexor on Osteoporosis Depends on Nuclear Accumulation of IκBα-NF-κB p65 Complex.

     Chen J, et al. · Front Pharmacol 2022;13:896108 2022
     used by RELA (p65) — menin binds it and represses it, and it is required to keep MLL oncoproteins on chromatin
182. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35893049
     Phenotypic Variation in Two Siblings Affected with Shwachman-Diamond Syndrome: The Use of Expert Variant Interpreter (eVai) Suggests Clinical Relevance of a Variant in the KMT2A Gene.

     Taha I, De Paoli F, Foroni S, Zucca S et al. · Genes (Basel) 2022
     used by SBDS - a ribosome-maturation factor whose loss causes a leukaemia-predisposition syndrome, and whose BioID neighbourhood contains AFF1, KMT2A, CDK9, PAF1 and LEDGF
183. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35124168
     Glucocorticoid receptor gene mutations confer glucocorticoid resistance in B-cell precursor acute lymphoblastic leukemia

     Tamai M, Kasai S, Akahane K, et al. · Journal of Steroid Biochemistry and Molecular Biology 2022
     used by SCMC-L1 (CVCL_7125) — a four-month-old's KMT2A::AFF1 line carrying NSD2 E1099K
184. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36450243
     SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia.

     Hoshii T, Perlee S, Kikuchi S, Rahmutulla B, Fukuyo M, Masuda T, Ohtsuki S, Soga T, Nabet B, Kaneda A · Cell Rep 2022
     used by SETD1A — a leukemia dependency whose enzyme activity turns out to be dispensable, The OXPHOS-dependent state — established in KMT2A-rearranged AML, and inverted in KMT2A-rearranged B-ALL where OXPHOS inhibition makes leukaemia-initiating cells appear, UROS: searched and empty — the scan's rank-15 hit has no leukemia literature, and no entry was written
185. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35061886
     SFPQ-ABL1 and BCR-ABL1 use different signaling networks to drive B-cell acute lymphoblastic leukemia.

     Brown LM, et al. · Blood Advances 2022
     used by SFPQ / PSF (P23246) - the last of 21 fusion-construct partners without an entry, and it is itself the 5' half of an ALL fusion that puts ABL1 in the nucleus
186. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34341479
     Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy.

     Pikman Y, Ocasio-Martinez N, Alexe G, et al., Stegmaier K · Leukemia 2022
     used by SHMT2 (P34897) - the mitochondrial one-carbon step, and the paralogue that rises while it falls is why its loss may not matter
187. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 35158202
     Assembly and interaction of core subunits of BAF complexes and crystal study of the SMARCC1/SMARCE1 binary complex.

     Dong C, Zhang R, Xu L, Liu B, Chu X, et al. · Biochem Biophys Res Commun 2022
     used by SMARCC1 / BAF155 (Q92922) - the SWI/SNF core scaffold, in the pan-MLL-fusion core, and the missing gene entry in this graph's SWI/SNF beat
188. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36335117
     The assembly of mammalian SWI/SNF chromatin remodeling complexes is regulated by lysine-methylation dependent proteolysis.

     Guo P, Hoang N, Sanchez J, Zhang EH, Rajawasam K, et al. · Nat Commun 2022
     used by SMARCC1 / BAF155 (Q92922) - the SWI/SNF core scaffold, in the pan-MLL-fusion core, and the missing gene entry in this graph's SWI/SNF beat
189. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35182972
     Osteopontin is required for the maintenance of leukemia stem cells in acute myeloid leukemia

     Zhou J, Chen X, Zhou P, et al. · Biochem Biophys Res Commun 2022
     used by SPP1 (osteopontin) - the endosteal matrix protein whose knockdown prolongs survival in MLL-AF9 mice, and the one KMT2A::AFF1-specific paper about it cannot be read
190. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35847518
     PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia.

     Tsai HI, Wu Y, Huang R, Su D, et al. · Acta Pharmaceutica Sinica B 2022
     used by SUV39H1 (O43463, KMT1A) - the H3K9me3 writer: a menin effector whose binding region OVERLAPS the drug pocket at its N-terminus, a tumour suppressor in MLL-AF9 AML, recruited to double-strand breaks by CTCF, and never localised at the KMT2A locus in any cell type
191. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
     AUGMENT-102: A Phase 1, Open-label, Dose-escalation Study to Evaluate Safety, Tolerability and Preliminary Anti-Leukemic Activity of SNDX-5613 in Combination With Chemotherapy in Patients With Relapsed/Refractory Leukemias Harboring Alterations in KMT2A/MLL, NPM1 and NUP98 Genes

     Syndax Pharmaceuticals · ClinicalTrials.gov 2022
     used by Syndax Pharmaceuticals — revumenib (SNDX-5613), the only menin inhibitor licensed down to infancy
192. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 35753676
     Chemical biology and pharmacology of histone lysine methylation inhibitors.

     Barghout SH, Machado RAC, Barsyte-Lovejoy D · Biochim Biophys Acta Gene Regul Mech 2022
     used by Tazemetostat - an approved EZH2 inhibitor, and the drug this disease's own biology predicts will not work
193. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 36056023
     Isoform-specific and ubiquitination dependent recruitment of Tet1 to replicating heterochromatin modulates methylcytosine oxidation.

     Arroyo M, Hastert FD, et al. · Nat Commun 2022
     used by TET1 (LCX / CXXC6) - a CXXC reader that is also a KMT2A fusion partner, and whose leukaemic fusion throws its own CXXC domain away
194. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 35288693
     Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia

     Khabirova E, Jardine L, Coorens THH, et al. · Nature Medicine 2022
     used by The corpus citation index reads `PMID nnnnnnnn` in prose and never the `pmid` citation field — it sees 1,908 of 3,991 papers, undercounts 872 of the rest, and its headline single-cell absence was an artefact, The early lymphocyte precursor (ELP) state — what KMT2A-rearranged infant B-ALL scores as against a developing bone marrow reference, and why it is earlier than the pro-B arrest this graph also records
195. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 35235040
     The economic impact of cancer diagnosis to individuals and their families: a systematic review

     Alzehr A, Hulme C, Spencer A, Morgan-Trimmer S · Supportive Care in Cancer 2022
     used by The cost the hospital never sees: half of families spend more than 15% of their income
196. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35172132
     DOT1L activity in leukemia cells requires interaction with ubiquitylated H2B that promotes productive nucleosome binding.

     Spangler CJ, Yadav SP, Li D, Geil CN, Smith CB, Wang GG, Lee TH, McGinty RK · Cell Rep 2022
     used by The DOT1L–ubiquitin and DOT1L–acidic-patch interfaces: two non-catalytic surfaces that MV4;11 cells cannot do without, The trans-histone crosstalk H2Bub → DOT1L → H3K79me: modulatory for me1, effectively required for me2/me3
197. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34927529
     Phase I trials of the lysine-specific demethylase 1 inhibitor, GSK2879552, as mono- and combination-therapy in relapsed/refractory acute myeloid leukemia or high-risk myelodysplastic syndromes

     · Leuk Lymphoma 2022
     used by The only two trials stopped on a stated risk-benefit judgement are GSK2879552 (LSD1) studies in AML, while iadademstat, another LSD1 inhibitor, ran a KMT2A-rearranged-enriched expansion with an acceptable safety profile - so the stop looks molecule-specific, and its reason is unread
198. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36552783
     Selective Menin Deletion in the Hippocampal CA1 Region Leads to Disruption of Contextual Memory in the MEN1 Conditional Knockout Mouse: Behavioral Restoration and Gain of Function following the Reintroduction of MEN1 Gene.

     Ulfat AK, Batool S, Iqbal F, Syed NI · Cells 2022
     used by The reversibility question: months of partial occupancy against a syndrome built from decades of loss, Turn menin off for a defined window, then back on: the missing experiment that would bound reversibility
199. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34174329
     The Intrinsically Disordered Proteins MLLT3 (AF9) and MLLT1 (ENL) - Multimodal Transcriptional Switches With Roles in Normal Hematopoiesis, MLL Fusion Leukemia, and Kidney Cancer

     · Journal of Molecular Biology 2022
     used by The same reader domain, mutated instead of fused, causes a childhood kidney tumour, The strongest published case that condensates are load-bearing in KMT2A-fusion leukemia — and it is AKAP95, not AFF1
200. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     The bone marrow niche regulates redox and energy balance in leukemia stem cells (GSE189928)

     GEO submitters · NCBI Gene Expression Omnibus 2022
     used by The unnamed osteolineage Cre is Prx1-Cre, which is not osteoblast-restricted - and that changes what the negative result means, The unstated-system worklist: 26 sources carry a caveat of this class, 18 now resolve, and 13 of 16 new resolutions are imports
201. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35735203
     Immunophenotypic characteristics of ZNF384 rearrangement compared with BCR-ABL1, KMT2A rearrangement, and other adult B-cell precursor acute lymphoblastic leukemia.

     Wang YZ, et al. · Cytometry B Clin Cytom 2022
     used by The ZNF384-fusion immunophenotype - weak CD10 with aberrant CD13/CD33 - and the one marker that separates it from KMT2A-rearranged disease runs the OPPOSITE way to expectation
202. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35796294
     TMPRSS13 zymogen activation, surface localization, and shedding is regulated by proteolytic cleavage within the non-catalytic stem region.

     Martin CE, Murray AS, Mackinder JR et al · Biological Chemistry 2022
     used by TMPRSS13 (MSPL) - a cell-surface serine protease fused in frame to KMT2A exon 20, the clearest NOT-APPLICABLE epigenetics call of the seven, and a symbol whose approved form has a third of its alias's recall
203. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35945419
     Structural and biochemical basis for DNA and RNA catalysis by human Topoisomerase 3beta.

     Yang X, et al. · Nature Communications 2022
     used by TOP3B (O95985) - the only human topoisomerase that works on RNA as well as DNA, delivered to the MYC promoter by an arginine mark, and it has poisons
204. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 36108750
     Phase separation of p53 induced by its unstructured basic region and prevented by oncogenic mutations in tetramerization domain.

     Chen C, Fu G, Guo Q, Xue S, Luo SZ · Int J Biol Macromol 2022
     used by TP53 - named in 84 entries of this graph, absent from the index genome study of the disease, and four different things depending on when you look
205. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35864958
     Maternal EHMT2 is essential for homologous chromosome segregation by regulating Cyclin B3 transcription in oocyte meiosis.

     Meng TG; Lei WL; Lu X; Liu XY; Ma XS; et al. · Int J Biol Sci 2022
     used by UNC0642 - the G9a/GLP chemical probe that abolished doxorubicin-induced Kmt2a copy gain in mice, and the one intervention in this beat that has been given to an animal
206. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 36380144
     Valemetostat Tosilate: First Approval.

     Keam SJ · Drugs 2022
     used by Valemetostat - an approved dual EZH1/EZH2 inhibitor that has already worked in an MLL-AF4 xenograft, in a disease nobody has enrolled it in
207. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34657763
     Vincristine dosing, drug exposure and therapeutic drug monitoring in neonate and infant cancer patients.

     Barnett S, Hellmann F, Parke E, Makin G, Tweddle DA, Osborne C, et al. · Eur J Cancer 2022
     used by Vincristine - measured to be no different in KMT2A-rearranged disease, and measured to be UNDERDOSED in infants by the very rule meant to protect them
208. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35021179
     Cleft Lip Palate in a Patient with 5q14.3 Deletion Syndrome: A Possible Unreported Feature?

     Fernández Hernández L, Alcántara Ortigoza MA, Ramos Angeles SE, González-Del Angel A · Cytogenetic and Genome Research 161:556-563 2022
     used by Where else in a child is the target switched on? (run)
209. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35713168
     Incidence and prognostic value of central nervous system involvement in infants with B-cell precursor acute lymphoblastic leukemia treated according to the MLL-Baby protocol

     Popov A, Tsaur G, Permikin Z, Fominikh V, Verzhbitskaya T, et al. · Pediatric Blood & Cancer 2022
     used by Where KMT2A-rearranged leukemia physically sits — marrow niche, CNS, blood, liver/spleen and skin
210. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 36010889
     Pediatric Precursor B-Cell Lymphoblastic Malignancies: From Extramedullary to Medullary Involvement

     Kroeze E, Arias Padilla L, Bakker M, Boer JM, Hagleitner MM, et al. · Cancers (Basel) 2022
     used by Where KMT2A-rearranged leukemia physically sits — marrow niche, CNS, blood, liver/spleen and skin
211. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35716125
     Expansion microscopy allows high resolution single cell analysis of epigenetic readers.

     Acke A, Van Belle S, Louis B, Vitale R, Rocha S, Voet T, Debyser Z, Hofkens J · Nucleic Acids Res 2022
     used by Where LEDGF/p75 actually is: bound to chromatin through mitosis, in the nuclear interior with H3K36me3 - and never once imaged in a KMT2A-rearranged cell
212. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35705031
     Oncogenic ZMYND11-MBTD1 fusion protein anchors the NuA4/TIP60 histone acetyltransferase complex to the coding region of active genes.

     Devoucoux M, Fort V, Khelifi G, Xu J, et al. · Cell Rep 2022
     used by ZMYND11::MBTD1 is the KMT2A-fusion architecture assembled from different parts - and the part it throws away is a direct physical brake on KMT2A itself, ZMYND11::MBTD1, t(10;17)(p15;q21) - a chromatin reader welded to the NuA4/TIP60 acetyltransferase, maintaining Hoxa/Meis1/Myb/Myc/Sox4 in AML: the KMT2A-fusion architecture built from different parts
213. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34588432
     Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements.

     Issa GC, Zarka J, et al. · Blood Cancer J 2021
     used by 172 adults with KMT2A-r AML: translocation subtype did not predict survival, so treat all KMT2A-r as adverse, One karyotype band, two partner genes: why t(11;19) and t(10;11) can cancel a real partner effect, The clinical outcome data do not support a single KMT2A class, and they do not refute the menin interface either
214. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34079125
     A proximity-dependent biotinylation map of a human cell.

     Go CD, et al. · Nature 2021
     used by A 109-transcription-factor BioID network puts KMT2A next to MYC, YY1 and the ETS and KLF families - and AF10 next to ERG and KLF5, A BioID hit is a neighbour, not a complex member - and the two methods are known to disagree, Proximity-interactome beat: every query run, every paper rejected, and the one resource not reachable
215. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34253594
     Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

     Rennert PD, ..., Ambrose C · Molecular Cancer Therapeutics 2021
     used by A CD19 CAR that secretes a CLEC12A bridge: aimed squarely at lineage switch, and it inherits both antigens' failure modes
216. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34550633
     KMT2A-MAML2 rearrangement emerged and regressed during neuroblastoma therapy without leukemia after 12.8-year follow-up.

     Felix CA, Slater DJ, Davenport JW, Yu X, Gregory BD, Li MM, Rappaport EF, Cheung NV · Pediatric Blood & Cancer 2021
     used by A child who made a KMT2A fusion during chemotherapy, lost it again, and never got leukaemia in 12.8 years, A KMT2A fusion is necessary but not sufficient: the cell it lands in decides whether there is a disease and which one, KMT2A::MAML2, inv(11)(q21q23) - a therapy-related fusion that also causes a solid tumour, MAML2 exon 2: the strongly preferred 3' acceptor, the same in leukaemia, thymoma and salivary-gland tumours
217. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33743795
     Reduction of RUNX1 transcription factor activity by a CBFA2T3-mimicking peptide: application to B cell precursor acute lymphoblastic leukemia.

     Jakobczyk H, Debaize L, Soubise B, Avner S, Rouger-Gaudichon J, Commet S, Jiang Y, Serandour AA, Rio AG, Carroll JS, Wichmann C, Lie-A-Ling M, Lacaud G, Corcos L, Salbert G, Galibert MD, Gandemer V, Troadec MB · J Hematol Oncol 2021
     used by A genuine small-molecule disruptor of an oncogenic oligomer DOES exist - 7.44 against the RUNX1::RUNX1T1 NHR2 tetramer - which corrects this graph's record; and its eighteen-year potency curve says the class is a chemistry problem, which is what this graph concluded for the wrong reason
218. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33562706
     Elucidating the Importance of DOT1L Recruitment in MLL-AF9 Leukemia and Hematopoiesis.

     Grigsby SM, Friedman A, Chase J, et al. · Cancers (Basel) 2021
     used by A long non-coding RNA binds DOT1L's catalytic domain and turns its activity up - and blocking it makes the fusion protein itself get eaten, Blocking where DOT1L binds instead of what it does - the modality that removes the mark only at fusion targets, Degrade DOT1L, inhibit DOT1L, or leave a dead enzyme in place - run all three against the same cells and the same marrow, DOT1L does things that have nothing to do with methylation - which is why blocking its active site was never going to remove all of it, DOT1L808 - a 5 nM DOT1L degrader that cleared an orthotopic leukaemia and still works after menin inhibitors fail, Normal blood needs DOT1L too - lose it in an adult mouse and the marrow fails within weeks
219. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34663924
     Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia

     Janssens DH, Meers MP, Wu SJ, Babaeva E, Meshinchi S, Sarthy JF, Ahmad K, Henikoff S · Nature Genetics 53:1586-1596 2021
     used by A pre-registered, institution-matched serial-pair replication: does a patient's own target set predict itself better than another child's does?, A target map read off the diagnostic sample does not describe the same child's disease after a lineage switch, An activity-stratified permutation null for promoter-set overlap, and the check that its hypergeometric shortcut is not an instrument bug, Analysis (runnable): is there a shared cell-state signature behind non-genetic menin-inhibitor and BET-inhibitor resistance?, Bivalent and primed chromatin at fusion target loci — and why the H3K4/H3K27 story is weaker than usually told, Bounded absence: in GSE159608's SEM line, VTP-50469 was profiled for H3K4me3 only - no menin, no H3K27ac, no H3K79me2, no RNAP2 and no IgG under the drug - and no library in the series carries a spike-in normalisation, so an absolute change in any mark is unmeasurable here, Census of every published chromatin-occupancy measurement made under a menin inhibitor: eight datasets, every one TSS-anchored, every one tabulating losses only, GSE159608 — 419 automated CUT&Tag libraries across 7 KMT2A-rearranged primary patient samples, 5 lines and a normal CD34+ donor, including KMT2A fusion occupancy, a menin-inhibitor arm in SEM, and three single-cell CUT&Tag libraries, H3K27me3 - the repressive mark this graph argued about for seventy-seven cycles without ever writing an entry for it, H3K4me3 - the mark KMT2A's own SET domain writes, that the fusion cannot write, that an interface in this graph already binds, and that switches PRC2 off, Hypothesis: the ceiling on menin-interface disruption is cell-state plasticity, not target mutation, In SEM, H3K4me3 responds to menin displacement the way a partially redundant mark should: selectively at menin-bound sites, by about a quarter, and not at all under a DOT1L inhibitor - which bounds how much of a menin inhibitor's lethality H3K4me3 can be carrying, Ranking bins by raw menin signal builds a class that the IgG control piles into eight to thirty-six fold - so the first version of our menin-bound contrast was measuring accessibility, and its own negative control said so before we believed it, Revumenib does not move H3K27me3 in MLL-fusion leukaemia, in vitro or in vivo: the absence narrows a THIRD time and the experiment's prior collapses, The H3K27me3 absence this graph keeps asserting is narrower than stated: the measurement exists, in the genetic arm of the paper the graph cites for the phenocopy, The obvious result was that VTP-50469 cuts H3K4me3 at HOXA9 three-fold in SEM. The pre-registered housekeeping control says GAPDH, RPL13A and TUBB fell just as far, so the obvious result was the normalisation, Trithorax against Polycomb at HOXA: the textbook antagonism, and the two ways this disease breaks it
220. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34113809
     The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia.

     Maat H, Atsma TJ, Hogeling SM, Rodriguez Lopez A, Jaques J, Olthuis M, et al. · iScience 2021
     used by A second disease finds the same DOT1L-to-non-canonical-PRC1 axis in the same year - and the mark moves the opposite way, H2AK119ub - the mark every PRC1.1 claim in this graph rests on, named in fifteen entries and written in none until now, TRIM27 - the E3 ligase inside PRC1.1 that USP7 spends its time undoing, and the worst UniProt localisation record this graph has audited, USP7 - the enzyme that holds PRC1.1 together, and the only pharmacological handle on this complex that exists today
221. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32733011
     Fusion of the CRM1 nuclear export receptor to AF10 causes leukemia and transcriptional activation of HOXA genes.

     Aumann WK, et al. · Leukemia 2021
     used by A ten-residue export signal is the 5' partner's whole contribution - and the field disagrees about which direction it pushes, CTCF keeps CALM-AF10 leukaemia undifferentiated through TGM2 - an architectural dependency, not a menin one, Export or docking? A locus-resolved H3K79me2 ChIP under an XPO1 inhibitor separates the two CALM-AF10 models, and it has never been run, SET::NUP214 is the second KMT2A-free HOXA fusion, and it converges on the same two proteins CALM-AF10 uses: CRM1 and DOT1L - and so does NPM1c, which IS menin-dependent (corrected 2026-09-21), The focal half: H3K79 hypermethylation at the HOXA cluster and MEIS1 - but which cluster member differs between CALM-AF10 and MLL-AF10
222. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34226546
     The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations.

     Klein BJ, et al. · Nat Commun 2021
     used by A ten-residue export signal is the 5' partner's whole contribution - and the field disagrees about which direction it pushes, How general is subtraction across KMT2A fusions? Common enough to matter, too heterogeneous to be one thing, and mostly invisible to the way this project searches, Import class 5: evidence borrowed from fusions that are not KMT2A fusions at all, Is the drug target always in the retained half? An audit of the project's own framing, Losing the AF10 PZP reader is not a missing function - it is a removed brake, and putting it back cures the fusion, MLLT10 (AF10) — DOT1L cofactor and KMT2A fusion partner, MLLT10 (AF10): the discarded PZP reader — the one partner where loss is proven to be the oncogenic event, MLLT10 / AF10 — domain architecture and residue coordinates, PICALM::MLLT10 (CALM-AF10), t(10;11)(p13;q14) - the DOT1L-dependent HOXA fusion that contains no KMT2A, Re-supply the AF10 PZP module in cis to KMT2A::MLLT10 and ask whether transformation is suppressed, Subtraction is a partner class, not a curiosity — and the class is defined by compartment, not by sequence, The KMT2A-r AML patient table numbers MLLT10 on isoform P55197-1, not the canonical sequence: S674 is S658 and S705 is S689
223. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33536240
     1,6-hexanediol rapidly immobilizes and condenses chromatin in living human cells

     Itoh Y, et al. · Life science alliance 2021
     used by A two-compartment switch for a SEC cargo: nucleolar retention versus AFF4-induced nucleoplasmic droplets, set by one methylated arginine, Counted absence: AFF1/AF4 - the partner in the commonest infant fusion - has no phase-separation literature under any alias, and the two hits that look like it are token collisions, ELL-EAF1: a phosphorylation-gated interface reported to drive phase separation - and the assays used cannot distinguish that from clustered binding, ENL's disordered region and condensates, restricted to what actually bears on KMT2A::MLLT1 - which is one figure panel, Nothing connects ENL YEATS binding or ENL condensates to phosphorylation: zero records, and what that means for the phase-2 dossier, NPM1 (nucleophosmin) — the nucleolar shuttle whose mutant form binds chromatin with KMT2A and buys the second menin-inhibitor indication, NUP98 FG condensates, audited assay by assay: no half-bleach has ever been done and no NUP98 fusion has ever been endogenously tagged, The only cellular proposal for how the SEC gets P-TEFb out of the reservoir is a condensate, and the two assays it rests on cannot tell that model from its rival
224. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34489550
     The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(4;11).

     Wilhelm A, Marschalek R · Oncogene 2021
     used by About one KMT2A-rearranged patient in twenty has no direct fusion at all - only the reciprocal one, AFF1::KMT2A (AF4-MLL), the der(4) product: what it is made of, residue by residue, At the DNA level almost every KMT2A-rearranged patient has a reciprocal allele - 94% across partners, and 5% have nothing else, Bounded absence: not one menin-inhibitor study, trial or preclinical paper has ever recorded reciprocal fusion status, Competing model 1: the reciprocal product starts the leukaemia and then leaves, Competing model 2: the reciprocal allele is lost as the leukaemia evolves, and losing it selects for something worse, Competing model 3: reciprocal status is a proxy for where the break fell, and the thing that changed is the DIRECT product, Forty-five percent of t(4;11) patients express a KMT2A fusion transcript that keeps the whole WRAD interface, Half of all KMT2A::MLLT1 patients make no reciprocal product at all - a ready-made control arm of about 240 people, In the only cohort that measured it, HOXA genes are ON in exactly the reciprocal-positive patients and OFF in the rest, Menin primacy was established on the der(11) product alone and has never been tested against the der(4) product, Put both fusion proteins in the same cell and you get something neither produces alone, Reciprocal status is a different fact depending on whether you assay DNA or RNA, and the whole prognostic literature is RNA, Stratify an existing menin-inhibitor cohort by reciprocal fusion status, The graph's universal 'every KMT2A fusion loses the SET domain' is a silent, propagating error class, The infant breakpoint mutilates the reciprocal protein's first PHD finger - so 'the reciprocal product' is at least two different proteins, Two classes of KMT2A rearrangement keep the SET domain, and the graph says otherwise
225. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33967269
     Tip60 activates Hoxa9 and Meis1 expression through acetylation of H2A.Z, promoting MLL-AF10 and MLL-ENL acute myeloid leukemia.

     Yamagata K, Shino M, Aikawa Y, Fujita S, Kitabayashi I · Leukemia 35(10):2840-2853 2021
     used by Acetylation is a cycle, not a mark - and this graph holds one complete cycle, on a residue the fusion throws away, Catalytic-dead versus degrader: a four-arm test that resolves the HDAC7 direction conflict and supplies the pharmacodynamic marker this drug class has never had, EP400 - the ATPase that swaps H2A.Z in; its complex is required by MLL leukaemia stem cells, and in DepMap it is one of the three genes LEAST required in KMT2A-rearranged lines, H2A.Z - two genes of identical length, one KMT2A paper, and the measured quantity is a ratio nobody has repeated, H2AZ1 - the one histone variant with a direct KMT2A-fusion paper: MLL-AF10 and MLL-ENL recruit Tip60 to Hoxa9 to acetylate H2A.Z, KAT5 / Tip60 - the acetyltransferase in the only direct KMT2A-fusion histone-variant result, and both fusions tested were myeloid
226. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34211097
     Favorable outcome of NUTM1-rearranged infant and pediatric B cell precursor acute lymphoblastic leukemia in a collaborative international study

     Boer JM, Valsecchi MG, Hormann FM, et al. · Leukemia 2021
     used by ACIN1::NUTM1 - the commonest NUTM1 fusion in infants, cryptic to cytogenetics, and the only one with a human cell line, BRD9::NUTM1, t(5;15)(p15.33;q14) - one fusion is enough to make infant B-ALL in a mouse, and it is the one that behaves best in a child, NUTM1 (NUT) - a testis-restricted, fully disordered protein that writes no mark and instead switches ON a writer, and the 3' partner of the KMT2A-wild-type infant B-ALL with the opposite prognosis, NUTM1-rearranged B-ALL - the KMT2A-wild-type arm of the same infant trials, with 4-year EFS of 100% against 36-37% next door
227. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34405474
     Assessing acute myeloid leukemia susceptibility in rearrangement-driven patients by DNA breakage at topoisomerase II and CCCTC-binding factor/cohesin binding sites.

     Atkin ND, Raimer HM, Wang Z, Zang C, Wang YH · Genes Chromosomes Cancer 2021
     used by Adjudicated: CTCF does not do opposite things at KMT2A - it does one thing, and this graph's contradiction is an untested premise about whether a break becomes a rearrangement, CTCF - named in the id of an existing entry in this graph and having no entry of its own, and the protein whose binding sites break preferentially in KMT2A-rearranged patients, CTCF/cohesin occupancy at the KMT2A exon-11 anchor is both the cause of the break and the chaperone of its correct repair - so losing it gives FEWER breaks and MORE rearrangements, Etoposide (VP-16) - the drug that makes this disease and cures several others, and the only entry in this graph whose main finding is that you must not stop using it, Experiment: degrade TOP2A and TOP2B separately in a fetal-like human progenitor and map DNA breaks at the KMT2A locus without a poison, Hypothesis: KMT2A and AFF1 break where they do because both breakpoint regions are CTCF/cohesin loop anchors sitting in the same nuclear hub, Put three descriptions of the same address on one hg38 axis - the exon-11 CTCF site, the intron-10/exon-11 functional cut point, and the region that breaks more in patients who got a KMT2A fusion - and find out whether they are one element, RAD21 - the cohesin subunit with the most break-prone sites in KMT2A-rearranged patients, and the degron experiment this graph keeps asking for, Run in coordinates: the protective CTCF site and the patient break-prone window are ONE element, it is cohesin-bound, and the 'functional cut point' is 3.75 kb away - two of the graph's three exon-11s were the same exon and the third was not, SMC3 - the cohesin ATPase arm, the only subunit whose partial loss has been tested directly against a KMT2A fusion, and it was tolerated, STAG2 - the cohesin subunit that defines secondary AML, and the one whose loss a KMT2A fusion does not care about, The CTCF site in KMT2A exon 11 - a conserved insulator element sitting exactly on the functional cut point of the breakpoint cluster region, whose occupancy decides whether the locus rearranges, The H3K9me1/2-CTCF brake: a KDM3B-G9a balance keeps the KMT2A breakpoint cluster region methyl-poor and CTCF-bound, and losing either end makes the locus amplify and rearrange - in epithelium, in primary cord-blood progenitors and in mice, The measurement that settles the CTCF dispute: degron-grade CTCF removal versus cohesin removal, with DNA breaks AND rearrangement outcome read out at the same 1 kb of KMT2A in the same cells, reported as rearrangements per break
228. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33411704
     Dynamic regulation of CTCF stability and sub-nuclear localization in response to stress.

     Lehman BJ, Lopez-Diaz FJ, Santisakultarm TP, Fang L, Shokhirev MN, Diffenderfer KE, Manor U, Emerson BM · PLoS Genetics 2021
     used by Adjudicated: CTCF does not do opposite things at KMT2A - it does one thing, and this graph's contradiction is an untested premise about whether a break becomes a rearrangement, CTCF - named in the id of an existing entry in this graph and having no entry of its own, and the protein whose binding sites break preferentially in KMT2A-rearranged patients, The H3K9me1/2-CTCF brake: a KDM3B-G9a balance keeps the KMT2A breakpoint cluster region methyl-poor and CTCF-bound, and losing either end makes the locus amplify and rearrange - in epithelium, in primary cord-blood progenitors and in mice, The measurement that settles the CTCF dispute: degron-grade CTCF removal versus cohesin removal, with DNA breaks AND rearrangement outcome read out at the same 1 kb of KMT2A in the same cells, reported as rearrangements per break, What the CTCF-protects paper actually cites: it names Gothe and Atkin in ONE direction-free sentence and declares the direction unresolved, and the two papers that ran the reciprocal experiment are absent from all 81 of its references
229. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33690798
     A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML.

     Chen BR, et al. · Blood 2021
     used by AF10 fusions recruit and stabilise JAK1 - a kinase bound to the fusion with no phosphosite on the fusion, JAK1 - recruited and stabilised by AF10 fusions, and the kinase whose downstream STAT1 the class I effect of menin inhibition explicitly does not need, MLLT10/AF10: twenty observed phosphosites, twelve PIKK motifs, and not one kinase-site relation in the literature - a bounded absence
230. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34373735
     Small-molecule inhibitor of AF9/ENL-DOT1L/AF4/AFF4 interactions suppresses malignant gene expression and tumor growth.

     Wu F, Nie S, Yao Y, Huo T, Li X, Wu X, Zhao J, Lin YL, Zhang Y, Mo Q, Song Y · Theranostics 2021
     used by AFF1 AF4_int motif to AF9/ENL AHD: the index fusion's only documented elongation interface, and it competes with DOT1L, Bite-back: a target nominated from an imported mechanism inherits a fusion the index disease does not have, Blocking where DOT1L binds instead of what it does - the modality that removes the mark only at fusion targets, Does KMT2A::AFF1 deliver DOT1L to the AHD or displace it? A competition experiment in t(4;11) cells, Import class 2: AHD-dependent mechanism, which cannot transfer because KMT2A::AFF1 has no AHD, KMT2A::AFF1 has no mapped interface to DOT1L: it lacks both structurally defined recruitment modules, and the one complex-level route claimed for it is contested by reconstitution, The AHD inhibitor's deposited arm is MOLM-13 and its in vivo arm is nowhere: a half-resolution that names the limit exactly
231. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33961781
     Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

     Huttlin EL, Bruckner RJ, Navarrete-Perea J, Cannon JR, Baltier K, Gebreab F, Gygi MP, Thornock A, et al. (28 authors), Gygi SP · Cell 2021
     used by AFF1/AFF4-CAMKV - DECLINED, and it is a LABELLED REDISCOVERY: data/symbol-collisions.json already holds a CAMKV row saying BioPlex 2017 and 2021 are one programme and that CAMKV is deposited under split isoform accessions, All nine unwritten MEN1 partners trace to exactly two publications, neither of which mentions menin outside an antibody catalogue row, DAXX - the strongest of five selective dependencies among 254 unwritten interactors but it FAILS Bonferroni correction (p=0.0128, rank 4 of 254), and not one paper connects it to this disease, DAXX and ATRX are absent from the only MLL-fusion AP-MS interactome - and PML is in it against all seven baits, alone, without a single one of its other body components, Diffing the core scaffold's curated interactome against the graph: 46 of 217 partners are things here, CDK9 is not one of them, and the filter I built to rank the rest was counting one platform twice, Fifth explanation for the Fanconi signal: it runs through menin binding FANCD2, not crosslink repair — tested, refuted, prior 0.07, JMY - one AP-MS row with AFF4, in HCT116 only, from a paper whose whole argument is that interactomes differ between cell lines, KMT2A-ABT1 is one spoke-expanded BioPlex 3.0 AP-MS row in HEK293T in which ABT1 is the bait and KMT2A the prey, and ABT1's nucleolus is ECO:0000250 only - declined, KMT2A-ANOS1 is one spoke-expanded BioPlex 3.0 AP-MS row with ANOS1 - a secreted, cell-membrane axon-guidance protein - as the bait and KMT2A as the prey in HEK293T - declined, KMT2A-FGFBP1 is spoke-expanded BioPlex 3.0 AP-MS recovered in BOTH HEK293T and HCT116 - it passes BioPlex's own replication criterion and the partner is a secreted extracellular protein - declined, KMT2A-KRR1 is one spoke-expanded BioPlex 3.0 AP-MS row in HEK293T with KRR1 as bait and KMT2A as prey, sitting in a seven-member ribosomal block at the floor score - declined, KMT2A-OASL is one spoke-expanded BioPlex 3.0 AP-MS row with OASL as bait and KMT2A as prey; OASL is the only partner in the beat natively expressed in blood leukocytes, and its nucleolar annotation is uncoded - declined, with the compartment argument unavailable, KMT2A-PRKRA is one spoke-expanded BioPlex 3.0 AP-MS row with PRKRA (PACT) as bait and KMT2A as prey; PRKRA's only UniProt compartments are cytoplasm and perinuclear region, both uncoded - declined, MEN1-CD226 is two proteome-scale AP-MS maps, both spoke-expanded, both in cell lines that do not express CD226 - declined, MEN1-ZC3HC1 is one spoke-expanded BioPlex row in HCT116, and UniProt records ZC3HC1 weakly or not expressed in leukocytes - declined, PBX2 - an AFF4 co-purifying protein in two rounds of one AP-MS atlas, and the PBX paralogue the leukaemia literature explicitly excluded
232. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33644933
     Phenotypic and protein localization heterogeneity associated with AHDC1 pathogenic protein-truncating alleles in Xia-Gibbs syndrome.

     Khayat MM, Li H, Chander V et al · Human Mutation 2021
     used by AHDC1 (Gibbin) - an AT-hook chromatin-architecture factor that is already a cofactor of a DIFFERENT sarcoma fusion oncoprotein, and whose KMT2A breakpoint lands in an untranslated exon
233. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33069783
     HOXA9/IRX1 expression pattern defines two subgroups of infant MLL-AF4-driven acute lymphoblastic leukemia

     Symeonidou V, Ottersbach K · Exp Hematol 2021
     used by An expression subgroup is not an occupancy subgroup — and this project keeps reading one as the other, GSE252378 deposits no transcriptional readout: all 171 samples are library_strategy OTHER and the metadata never says RNA, so every programme claim from this deposit is occupancy and none is expression, GSE252378 holds eight KMT2A::AFF1 oncoprotein panels from two centres, not the three this corpus had used, HOXA9/HOXA10 is unoccupied and unmethylated at H3K4 in two of the three primary infant KMT2A::AFF1 states, while the SEM cell line carries the strongest AFF1 signal over that locus of any sample in the deposit, iALL-HOXA9 — the HOXA-high state of infant KMT2A::AFF1 ALL, and the one everything is modelled on, iALL-IRX1 — the HOXA-negative, IRX1-high state of infant KMT2A::AFF1 ALL, IRX1 — Iroquois homeobox 1, the gene that names the HOXA-negative half of infant t(4;11) ALL, IRX1 carries the KMT2A::AFF1 oncoprotein in exactly the patients where HOXA does not — seven patients, GSE252378, Is IRX1 expressed in normal blood at all? Two of the three papers say no, one says exclusively yes, p279 carries the oncoprotein at HOXA AND at IRX1 — the published mutual exclusivity is not mutual exclusivity at chromatin, PROM1 (CD133) occupancy tracks HOXA occupancy at Spearman +0.952 — a second, independent marker of the same split, SEM, the standard t(4;11) model line, has zero signal at IRX1 — every model of this disease is a model of one subgroup, Single-cell CUT&Tag on p279 — is the double-positive blast one cell state or two clones?, The HOXA/IRX1 mutual exclusivity is reproduced at the transcript level in 48 KMT2A::AFF1 infant ALL cases (Fisher two-sided p < 1e-6) and is ABSENT in KMT2A::MLLT1 and in KMT2A-germline controls
234. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33983906
     Integrative methylome-transcriptome analysis unravels cancer cell vulnerabilities in infant MLL-rearranged B cell acute lymphoblastic leukemia

     Tejedor JR, Bueno C, Cobo I, et al. · Journal of Clinical Investigation 2021
     used by Analysis (runnable): build a methylome cell-of-origin score for infant KMT2A-rearranged ALL and test it as a predictor of lineage destination, Analysis (runnable): does the infant methylome predict HOXA status once age and breakpoint are controlled?, Hypothesis: genetic and non-genetic escape from menin inhibition are substitutes, so MEN1 mutations will be rare in infants and the field's resistance biomarker will fail in children, Hypothesis: the cell-of-origin methylome, not the breakpoint, decides whether a KMT2A::AFF1 leukemia is HOXA-high or HOXA-low, Hypothesis: where a blast goes when the fusion program is released is written in its methylome at diagnosis, not in its transcriptome, Pentimento and restoration — the fusion overpaints the cell, and cleaning reveals whatever was underneath, Plain-English: chromatin and epigenetics — the sticky notes on the DNA, and which ones matter here, Portfolio theory — a hedge only works against uncorrelated risk, and nobody has estimated the correlation matrix of resistance routes, The KMT2A-r DNA methylation signature — focal hypermethylation, no global hypomethylation, and a hypomethylating agent that did not help, The near-silent genome of infant KMT2A-r ALL — 1.3 non-silent mutations, and why that is bad news as well as good
235. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33405950
     Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol

     Stutterheim J, van der Sluis IM, de Lorenzo P, et al., Pieters R · Journal of Clinical Oncology 2021
     used by Analysis: is the KMT2A genomic breakpoint a prognostic variable? A reanalysis of data Interfant and Frankfurt already hold, Collaborate or compete: an honest matrix, including where the lab would be duplicating a better-resourced effort, ctDNA MRD under a menin inhibitor: blood flow diverges from blood DNA, because the disease is in the spleen and marrow, External and historical controls: the design infant leukemia actually uses, How many children this affects, Hypothesis: the KMT2A genomic breakpoint carries prognostic information that the field has been sitting on for twenty years, Ig-based MRD fails specifically in the KMT2A-rearranged patients whose IGH repertoire is proximally biased and still recombining, Is reciprocal status or breakpoint position used in MRD design or risk stratification? Once, by necessity, in 16 of 3,401 patients - and nowhere in any risk model, Join the KMT2A breakpoint archive to the Interfant MRD and outcome database, on patient, MRD as a trial endpoint in KMT2A-rearranged leukaemia: high negativity rates, and almost none of them say which assay, MRD by fusion transcript: fast, standardised, partner-limited - and structurally blind to KMT2A*, MRD by genomic breakpoint: the only assay in this disease that is fusion-specific by construction, MRD by Ig/TCR rearrangement: the standard in ALL, and the assay infant KMT2A-rearranged disease strains hardest, Open ground: the questions in this graph that nobody in the landscape appears to be working on, Proximally biased V(D)J and IGHV6-1 in KMT2A::AFF1: the Ig MRD target is a moving target, and the clinic had already moved, Retrospective paired-target MRD on stored Interfant marrows, stratified by IGHV usage, Rob Pieters, Inge van der Sluis & the Interfant consortium (Princess Maxima Center, Utrecht) — the only global infant-ALL trial network, Sequencing-based MRD: better than flow in paediatric B-ALL, and applied to infant KMT2A-rearranged disease exactly once, The Interfant-06 backbone, phase by phase: what the protocol every infant reference in this graph points at actually does, The MRD target a centre can run decides which infants are intensified, and the two targets disagree in the direction that matters, WBC 300: a stratification convenience, not a biological threshold - and the evidence says so four different ways, What MRD-negative actually means: a quantitative range, a laboratory judgement, and three incompatible definitions, Which MRD timepoint drives which decision in infant ALL, and how good the evidence for each is, Who holds the data and samples we cannot generate ourselves — an access map
236. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34824279
     A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program

     Rice S, Jackson T, Crump NT, Fordham N, Elliott N, O'Byrne S, Lara Fanego MDM, Addy D, Crabb T, Dryden C, Inglott S, Ladon D, Wright G, Bartram J, Ancliff P, Mead AJ, Halsey C, Roberts I, Milne TA, Roy A · Nature Communications 2021
     used by Analysis: score fetal, myeloid-priming and differentiation-stage signatures across public KMT2A-r datasets, Bone marrow haematopoietic stem cell — the postnatal comparator, and why the same fusion behaves differently here, CRISPR-engineered t(4;11) in human fetal liver — the only model that reproduces infant-specific biology, Fetal liver haematopoietic stem and progenitor cell — the leading candidate cell of origin for t(4;11) infant ALL, SEM (CVCL_0095) — the workhorse, from a five-year-old, and microsatellite unstable
237. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34088716
     A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes

     Harman JR, Thorne R, Jamilly M, Tapia M, Crump NT, Rice S, Beveridge R, Morrissey E, de Bruijn MFTR, Roberts I, Roy A, Fulga TA, Milne TA · Genome Research 2021
     used by Analysis: score fetal, myeloid-priming and differentiation-stage signatures across public KMT2A-r datasets, Experiment: is the primed state in KMT2A::AFF1 actually bivalent? Multi-mark CUT&Tag on primary infant blasts, Hypothesis: releasing the KMT2A::AFF1 differentiation block sends cells toward myeloid, not mature B, in a measurable fraction of infant cases, Step 5 — The output program: HOXA9/HOXA10/MEIS1/PBX3 plus MEF2C, MYB, BCL2, FLT3 and PROM1/CD133, The differentiation block — what it actually is, operationally, in KMT2A::AFF1 leukaemia, The primed chromatin state — what is actually established, and why the word 'bivalent' should be used carefully here, The pro-B arrest state — what a KMT2A::AFF1 blast is actually doing while it sits there
238. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34194047
     Shape of promoter antisense RNAs regulates ligand-induced transcription activation

     Yang F, Tanasa B, Micheletti R, Ohgi KA, Aggarwal AK, Rosenfeld MG · Nature 2021
     used by ANSWERED from the paper's own methods, not from the corresponding author: the `dsgf` token that splits GSE139196's four SUV39H1 tracks into the two high and the two low ones is DSG-plus-formaldehyde double crosslinking - so the 44.5-percentile spread Q114 reported is a protocol variable, not replicate noise, GSE139196: SUV39H1 ChIP-Seq in MCF-7 with and without 40 minutes of estradiol - a ligand-inducible SUV39H1 occupancy experiment, filed under the retired symbol KMT1A in its own sample titles, RUN, with its positive control: knocking down KDM4B and KDM4C together raises H3K9me3 at the +1 nucleosome of 2,000 active promoters by 35.7 percentile points, moves the KMT2A promoter's +1 nucleosome by the same 35.3, and moves the 90 kb KMT2A gene body 5.05 points the WRONG way - so the methyl-poor domain is not an erasure product, RUN: endogenous HP1a/CBX5 is DEPLETED at the exon-11 anchor (median 23.94th percentile) and has the lowest KMT2A gene-body reading of any protein in the panel (30.16) - while the phosphomimetic Bio-ChIP mutant 4E reads higher than the phospho-compromised 4A at all seven intervals AND that difference falls inside the genome-wide interquartile range of the same comparison, so it carries no information, RUN: G9a/EHMT2 reads the 95.8th percentile of 56,171 same-cell-type CTCF anchors at the KMT2A promoter in all four MCF-7 ChIP-seq tracks, and a median 33.42nd at the exon-11 anchor - so the cheapest test of hyp-q114's third prediction REFUTES it, RUN: KAP1/TRIM28 has a called peak overlapping the KMT2A promoter in MCF-7 in both hormone conditions, 267 bp of it inside the K562 TRIM28 peak Q110 found - and its nearest chr11 peak to the exon-11 CTCF summit is 52,230 bp away, RUN: KDM4B and KDM4C both read the 76.6th-79.7th percentile of MCF-7 CTCF anchors over the whole 90 kb KMT2A gene body - above the 25-track panel median of 61.39, LOCUS-WIDE ELEVATED - and both are ORDINARY at the exon-11 anchor with replicate spreads of 92.3 and 61.5 percentile points, The deposit this graph filed as 'four SUV39H1 ChIP-seqs' is actually 77 samples in MCF-7 carrying the ENTIRE H3K9 axis in one cell type and one pipeline - writer SUV39H1, writer G9a/EHMT2, reader HP1-alpha/CBX5 (wild-type AND two phospho-mutants), co-repressor KAP1/TRIM28, erasers KDM4B and KDM4C, the mark H3K9me3, and an shKDM4B+shKDM4C eraser-knockdown arm, The GEO sweep that q110 named as free and did not run: SUV39H1 chromatin occupancy HAS been measured in two human cell types, six samples, hg38 bigWigs already deposited - so the writer half of the H3K9me3 absence is measured-not-analysed, not never-measured
239. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33640491
     Proximity-dependent Mapping of the Androgen Receptor Identifies Kruppel-like Factor 4 as a Functional Partner.

     Vélot L, et al. · Mol Cell Proteomics 2021
     used by AR / androgen receptor - the best-supported partner in the absence set by independent-publication count, and the reason a menin inhibitor is in prostate cancer trials
240. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34012049
     Mechanism for DPY30 and ASH2L intrinsically disordered regions to modulate the MLL/SET1 activity on chromatin.

     Lee YT, Ayoub A, Park SH, et al. · Nat Commun 2021
     used by ASH2L SPRY and RBBP5 347-356: a phospho-reader contact gated by RbBP5 Ser350, and the only WRAD interface with a measured fold-change, DPY30 D/D domain and the ASH2L SDI helix: four hydrophobic pockets, one load-bearing leucine - and a 94-residue numbering offset that relocates the whole motif
241. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34263728
     Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia.

     Richter WF, Shah RN, Ruthenburg AJ · Elife 2021
     used by At low drug doses the leukaemia dies through FLT3, not through HOXA9 - a second H3K79me2 pathway the dose-response hides, Bivalent and primed chromatin at fusion target loci — and why the H3K4/H3K27 story is weaker than usually told, DOT1L was not refuted - the wrong thing was blocked, at a dose nobody finished escalating, Experiment: build the missing KMT2A::AFF1 degron and titrate it — what fractional occupancy does the program actually need?, Measure all three H3K79 states on a real scale, across a dose series and after a menin inhibitor - the measurement this whole field has been doing by proxy, MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed, Plain-English: chromatin and epigenetics — the sticky notes on the DNA, and which ones matter here, Step 5 — The output program: HOXA9/HOXA10/MEIS1/PBX3 plus MEF2C, MYB, BCL2, FLT3 and PROM1/CD133
242. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     GSE159608 - Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia (419 GSMs; CD34+ HSPC KMT2A N1/N2/C1/C2 AutoCUT&RUN, hg19)

     Janssens DH, Henikoff S (Fred Hutchinson Cancer Center) · NCBI Gene Expression Omnibus 2021
     used by At promoter resolution the published N/C oncoprotein criterion calls 1043 promoters in fusion-negative CD34+ HSPCs - above the median across 27 KMT2A-rearranged patients - while the same-reagent controls in that sample call 66 and 11, Bounded absence: every chromatin measurement under a menin inhibitor is in an adult-derived line, and none is in an infant KMT2A::AFF1 model, Bounded absence: in GSE159608's SEM line, VTP-50469 was profiled for H3K4me3 only - no menin, no H3K27ac, no H3K79me2, no RNAP2 and no IgG under the drug - and no library in the series carries a spike-in normalisation, so an absolute change in any mark is unmeasurable here, Defect report: analyses/does-this-deposit-agree-with-itself/run.py keys each GEO record on !Sample_geo_accession, which in a SOFT record comes AFTER !Sample_title - one line, and it inverted the finding, Experiment: a 6 / 24 / 72 hour / 7 day VTP-50469 time course in SEM reading menin occupancy and H3K4me3 together, to decide whether the 23% is a partial effect or a slow one, Experiment: spike-in-normalised H3K4me3, menin and IgG CUT&Tag in SEM under VTP-50469 and EPZ-5676 - the one missing experiment that turns every ratio in this beat into an absolute number, Forty-one SEM libraries in GSE159608 sort themselves by antibody from the signal alone, across two protocols, two operators and ten months - so the deposit's own labels are confirmed by an instrument that does not share the labels' failure mode, GSE159608 — 419 automated CUT&Tag libraries across 7 KMT2A-rearranged primary patient samples, 5 lines and a normal CD34+ donor, including KMT2A fusion occupancy, a menin-inhibitor arm in SEM, and three single-cell CUT&Tag libraries, Hypothesis: the three quarters of H3K4me3 that survive menin displacement at fusion target sites are held by a menin-independent complex, and identifying it names the combination partner for a menin inhibitor, In an unsupervised 5 kb correlation of 41 SEM libraries, both KMT2A N-terminal AutoCUT&RUN libraries have menin as their single nearest neighbour - the menin-interface hypothesis appearing as the top-level structure of an analysis that was not looking for it, In SEM, H3K4me3 responds to menin displacement the way a partially redundant mark should: selectively at menin-bound sites, by about a quarter, and not at all under a DOT1L inhibitor - which bounds how much of a menin inhibitor's lethality H3K4me3 can be carrying, In SEM, the infant-derived KMT2A::AFF1 line, VTP-50469 lowers H3K4me3 at menin-bound sites by 23% relative to H3K4me3-matched menin-free sites (95% CI 13-33%), while the DOT1L inhibitor EPZ-5676 changes it by 1% (CI -4 to +6%), Ranking bins by raw menin signal builds a class that the IgG control piles into eight to thirty-six fold - so the first version of our menin-bound contrast was measuring accessibility, and its own negative control said so before we believed it, The 'sixteen percent of GEO sample labels contradict their own metadata' finding is a one-line off-by-one: 2,280 of 2,280 titles were attributed to the wrong sample, and with the record boundary fixed the rate falls from 96 of 586 comparable pairs (16.4%) to 7 of 656 (1.1%) - and all seven, read by hand and named here, are tokeniser artefacts rather than contradictions, The CD34+ oncoprotein-negative sample that calibrates the published N/C threshold is in GSE159608, not GSE252378 - so the 1.75 threshold cannot be re-derived from the deposit that carries the 27 patients it is applied to, The KMT2A C-terminal site class gives VTP-50469/DMSO = 1.13 - an apparent GAIN of H3K4me3 - and its IgG negative control sits at 2.4-2.6, so the class is background and the number must not be reported as a result, The N-over-C oncoprotein score is not fusion-specific by construction, because taspase1 cleaves wild-type KMT2A into an N320 and a C180 fragment that need not occupy the same chromatin - so a fusion-negative cell has a real N/C signal, The obvious result was that VTP-50469 cuts H3K4me3 at HOXA9 three-fold in SEM. The pre-registered housekeeping control says GAPDH, RPL13A and TUBB fell just as far, so the obvious result was the normalisation, The only second mark with a drug arm in SEM is H3K27ac, and its replicates agree at r = 0.21-0.29 against H3K4me3's 0.78-0.83 - so GSE159608's SEM EPZ-5676 experiment has one usable readout, not two, The two VTP-50469 H3K4me3 libraries hold 3.3% and 3.8% of their reads in the DMSO-defined peak set against 8.9% for DMSO and 9.4% for EPZ-5676 - one global fact that explains every raw locus difference in the SEM menin-inhibitor arm, and that cannot be resolved into drug effect or library quality
243. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33741715
     EWS-FLI1 and Menin Converge to Regulate ATF4 Activity in Ewing Sarcoma.

     Jimenez JA, Apfelbaum AA, Hawkins AG, Svoboda LK, et al. · Molecular Cancer Research 2021
     used by ATF4 / CREB2 (P18848) - the hub this graph inferred from its targets and never wrote, and its own transcript does not move under either menin inhibitor, PHGDH (O43175) - the largest menin-SELECTIVE fall in the whole serine panel, and the least essential gene in it, The 24 genes that respond to BOTH menin inhibitors in RS4;11 are led by the ATF4 stress programme - CHAC1 -5.11, STC2 -4.40, TRIB3 -3.10 - and CHAC1 and TRIB3 are named zero times in this graph, The ATF4/ISR collapse under menin inhibitors reports loss of the KMT2A-fusion transcriptional programme by ANY route, not engagement of the menin interface - and the loss is of ATF4 activity, not ATF4
244. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34936448
     Loss of ATF4 leads to functional aging-like attrition of adult hematopoietic stem cells.

     Sun Y, Lin X, Liu B, Zhang Y, et al. · Science Advances 2021
     used by ATF4 / CREB2 (P18848) - the hub this graph inferred from its targets and never wrote, and its own transcript does not move under either menin inhibitor
245. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33731875
     Histone H2Bub1 deubiquitylation is essential for mouse development, but does not regulate global RNA polymerase II transcription.

     Wang F, El-Saafin F, Ye T, Stierle M, Negroni L, Durik M, Fischer V, Devys D, Vincent SD, Tora L · Cell Death Differ 2021
     used by ATXN7L3 — the shared adaptor that actually sets H2Bub levels, and a KMT2A-selectivity hit nobody in this field has looked at, Erasing H2Bub: three deubiquitinases share two adaptors, and removing the enzyme the field names lowers the mark instead of raising it
246. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33456567
     KDM6A promotes imatinib resistance through YY1-mediated transcriptional upregulation of TRKA independently of its demethylase activity in chronic myelogenous leukemia

     See PubMed record PMID 33456567 for the full author list (not transcribed here) · Theranostics 2021
     used by Auditing the seven strikes before applying them: nine of ten decisions stand, four for different reasons than were given, and one clinical argument fails, One experiment that decides whether KDM4C is a target or the KDM4 family is: paralogue rescue of SD70 sensitivity in SEM
247. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34262032
     SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade

     See PubMed record PMID 34262032 for the full author list (not transcribed here) · Nature Communications 2021
     used by Auditing the seven strikes before applying them: nine of ten decisions stand, four for different reasons than were given, and one clinical argument fails
248. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33692463
     Clinical characteristics and outcomes of B-ALL with ZNF384 rearrangements: a retrospective analysis by the Ponte di Legno Childhood ALL Working Group.

     Hirabayashi S, Butler ER, Ohki K, Kiyokawa N, Bergmann AK, Moricke A, Boer JM, Cave H, Cazzaniga G, Yeoh AEJ, et al., Moorman AV, Manabe A · Leukemia 2021
     used by BMP2K (BIKe) - a nuclear serine/threonine kinase, and the ZNF384 fusion partner that is not a chromatin protein, BMP2K::ZNF384 - a PROTEIN KINASE as the 5' partner, with its catalytic domain retained: the counterexample to 'the partner is always a chromatin coactivator', EP300::ZNF384 - the commonest ZNF384 fusion, and it throws away the acetyltransferase, EWSR1::ZNF384 - the same EWSR1 exon 7 fragment that drives Ewing sarcoma, fused instead to a zinc-finger protein, in B-ALL, EWSR1::ZNF384 versus EWSR1::FLI1 - the same EWSR1 exon-7 module on two different DNA-binding proteins, and nobody has compared them, Lineage switch to myeloid leukaemia under CD19-directed therapy in ZNF384-rearranged ALL - and in the one cohort that caught both families, the ZNF384 switch looked mutationally NOTHING like the KMT2A ones, TAF15::ZNF384 - the FET-partner version, where the naming order in the literature is a trap and the founding experiment says the transactivation domain is not doing the work, TCF3::ZNF384 - the partner whose contribution is now actually demonstrated: steroid resistance, and it is not shared with EP300::ZNF384, The ZNF384 family is not the inverse of KMT2A::AFF1 - it is the SAME grammar written in the opposite gene order, and three of the four claims in the inverse framing are false, The ZNF384-fusion immunophenotype - weak CD10 with aberrant CD13/CD33 - and the one marker that separates it from KMT2A-rearranged disease runs the OPPOSITE way to expectation
249. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33108353
     ANGPTL2-containing small extracellular vesicles from vascular endothelial cells accelerate leukemia progression

     Huang D, Sun G, Hao X, He X, Zheng Z, Chen C, et al. · Journal of Clinical Investigation 2021
     used by Bone-marrow sinusoidal endothelial cell — the vessel wall that keeps stem cells alive, and posts vesicles that accelerate MLL-AF9 leukaemia, The perivascular and sinusoidal niche — where the functional evidence actually sits, and where the marrow is genuinely hypoxic
250. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33599085
     Bortezomib suppresses self-renewal and leukemogenesis of leukemia stem cell by NF-ĸB-dependent inhibition of CDK6 in MLL-rearranged myeloid leukemia.

     Zhou B, Qin Y, ... Gao S · Journal of Cellular and Molecular Medicine 2021
     used by Bortezomib is called an NF-kB inhibitor, and in MLL leukaemia it does two different things in two lineages — neither of which is reliably NF-kB in the lymphoid one
251. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33821572
     Menin-regulated Pbk controls high fat diet-induced compensatory beta cell proliferation.

     Ma J, Xing B, Cao Y, He X, et al. · EMBO Molecular Medicine 2021
     used by Both approved menin inhibitors cause multi-organ hyperplasia in animals, and one of them in the pancreas irreversibly, Four different ways to lose menin, and the graph has been treating them as one, How long does menin have to be gone? Two months in a mouse islet, a decade or more in a human carrier, How menin holds the beta cell still: JunD recruits it, with HDAC3, onto the Pbk promoter, Hypothesis: the same drug is protective in the islet and harmful in the parathyroid and the growth plate, Pancreatic neuroendocrine tumours in MEN1: the manifestation that kills, and the one the animal data points at, The same drug target, pursued for benefit: menin inhibition is a diabetes strategy in the literature, Three extra tubes: the glucose study that answers the inversion in children, Twelve weeks of a menin inhibitor in diabetic mice: more beta cells, lower fasting glucose, and nobody looked for a tumour
252. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33594072
     ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism.

     Li J, Galbo PM, Gong W, Storey AJ, et al. · Nat Commun 2021
     used by Both MBTD1 fusions end at H3K27me3-poor chromatin, one by excluding PRC2 and one by poisoning it - so the shared endpoint is the phenotype and MBTD1 is the coincidence, EPC1 - the NuA4/TIP60 subunit whose C-terminal fragment grips MBTD1, making it the contact a leukaemic fusion cannot do without and the mildest dependency in that whole complex, MBTD1 - the H4K20me1/me2 reader inside NuA4/TIP60, the quiescence brake on adult haematopoietic stem cells, and the 3' partner of ZMYND11::MBTD1 whose methyl-lysine cage the fusion carries and does not use, MBTD1 is the effector-recruiting half of a leukaemia fusion and the addressing half of a sarcoma fusion while donating nearly all of itself to both - so the junction, not the parts, assigns the role, MBTD1::EZHIP (MBTD1-CXorf67), t(X;17)(p11.2;q21.33) - MBTD1's other fusion, in which a NuA4 subunit delivers an H3K27M-mimicking PRC2 poison to low-grade endometrial stromal sarcoma, Three blots and one drug curve: does the ZMYND11::MBTD1 fusion protein still bind KMT2A, and does a menin inhibitor work in a leukaemia with no KMT2A rearrangement, ZMYND11 (BS69) - an H3.3K36me3 reader that restrains elongation, is itself the 5' partner of a chromatin-hijacking AML fusion driving HOXA/MEIS1/MYB, and whose promoter is the third-strongest MLL1-N bin in RS4;11, ZMYND11::MBTD1 AML is menin-inhibitor sensitive despite having no KMT2A rearrangement, because the translocation deletes ZMYND11's MYND domain and with it a physical brake on wild-type KMT2A, ZMYND11::MBTD1 is the KMT2A-fusion architecture assembled from different parts - and the part it throws away is a direct physical brake on KMT2A itself, ZMYND11::MBTD1, t(10;17)(p15;q21) - a chromatin reader welded to the NuA4/TIP60 acetyltransferase, maintaining Hoxa/Meis1/Myb/Myc/Sox4 in AML: the KMT2A-fusion architecture built from different parts
253. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34551297
     DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferation.

     Song T, Zou Q, Yan Y, Lv S, Li N, Zhao X, Ma X, Liu H, Tang B, Sun L · Cell Rep 2021
     used by Bounded failure with a near-miss worth recording: a GEO series matching the topic exactly belongs to a different paper, How much sugar the cell has decides how much DOT1L there is - a metabolic dial on the leukaemia's mark
254. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34877491
     TIFAB accelerates MLL-AF9-Induced acute myeloid leukemia through upregulation of HOXA9.

     Zhao J, Xiu Y, ... Zhao C · iScience 2021
     used by Canonical versus non-canonical NF-kB in KMT2A-rearranged leukaemia — the two arms have opposite signs, and the two papers usually read as contradicting each other actually agree, Is TIFAB a direct RelB target? Two papers in the same MLL-AF9 system answer differently, RELB — the NF-kB subunit that SUPPRESSES MLL-AF9 leukaemia, with a direct ChIP target list and a genetic rescue, which makes it the best-evidenced anti-leukaemic node in this beat, TIFAB — a 161-residue NF-kB adaptor-layer protein with TWO direct KMT2A-fusion papers, which is more disease-specific evidence than any receptor or TRAF in this beat has
255. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33412112
     CARM1 regulates replication fork speed and stress response by stimulating PARP1.

     Genois MM, Gagné JP, et al. · Molecular Cell 2021
     used by CARM1 / PRMT4 (Q86X55) - the H3R17me2a writer, and the enzyme whose product is read by the KMT2A C-terminus that every fusion deletes
256. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33067614
     A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)

     Brivio E, Locatelli F, Lopez-Yurda M, et al. · Blood 2021
     used by CD22-directed therapy (inotuzumab ozogamicin) — the second B-lineage antigen, with high response and poor durability
257. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34048275
     Gemtuzumab Ozogamicin Improves Event-Free Survival and Reduces Relapse in Pediatric KMT2A-Rearranged AML: Results From the Phase III Children's Oncology Group Trial AAML0531.

     Pollard JA, ..., Gamis AS · J Clin Oncol 2021
     used by CD33 (SIGLEC3) - the aberrant myeloid antigen on a B-lineage blast, and the one antibody-drug-conjugate target with a positive randomised result in KMT2A-rearranged disease, Myeloid-directed antigens (CD33, CD123) — the only immunotherapy axis that survives lineage switch, One trial, two published analyses, never crossed: gemtuzumab clearly helps KMT2A-rearranged children, and a common CD33 genotype abolishes gemtuzumab benefit — nobody has asked whether it abolishes it in them
258. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33623141
     FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children's Oncology Group trial AALL0631.

     Brown PA, Kairalla JA, Hilden JM, et al. · Leukemia 2021
     used by Central nervous system involvement at diagnosis in KMT2A-rearranged infant leukaemia, COG AALL0631 — lestaurtinib in infant KMT2A-rearranged ALL: negative overall, positive where the drug actually hit, FLT3 / CD135 — the strongest non-tether co-dependency, and a target the field may have written off on a badly executed trial, Hyperleukocytosis: why a very high white-cell count is a medical emergency, Infant acute lymphoblastic leukaemia (ALL diagnosed under 1 year of age), Which partner, in which patient: KMT2A partner frequencies across six age-lineage strata
259. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33651090
     Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial

     Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, et al. · JAMA 2021
     used by Children's Oncology Group — the trial network, the AALL protocol series and the biobank that no single lab can substitute
260. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33094319
     CLEC12A and CD33 coexpression as a preferential target for pediatric AML combinatorial immunotherapy.

     Willier S, Rothamel P, Hastreiter M, Wilhelm J, Stenger D, Blaeschke F, et al. · Blood 2021
     used by CLEC12A (CD371, CLL-1, MICL) - the leukaemic-stem-cell antigen whose therapeutic rationale rests on an absence, and which menin inhibition appears to induce
261. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.trial_registry
     Randomization of Highest Risk Infants to Intensive Chemotherapy +/- FLT3 Inhibition (CEP-701, Lestaurtinib)

     Children's Oncology Group · ClinicalTrials.gov 2021
     used by COG AALL0631 — lestaurtinib in infant KMT2A-rearranged ALL: negative overall, positive where the drug actually hit
262. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     GEO series GSE178569 (MACE-Seq) and GSE178567/GSE178568 (ATAC-Seq), deposited for the t(4;11) hit-and-run study

     Wilhelm A, Marschalek R · NCBI GEO 2021
     used by Competing model 1: the reciprocal product starts the leukaemia and then leaves
263. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33749383
     Lineage Switch in an Infant B-Lymphoblastic Leukemia With t(1;11)(p32;q23); KMT2A/EPS15, Following Blinatumomab Therapy.

     Du J, Chisholm KM, Tsuchiya K, et al. · Pediatric and Developmental Pathology 2021
     used by Competitive release and adaptive therapy — what ecology says happens when you remove the dominant species, Hypothesis: releasing the KMT2A::AFF1 differentiation block sends cells toward myeloid, not mature B, in a measurable fraction of infant cases, Hypothesis: the myeloid clone that appears after CD19-directed therapy was already there at diagnosis, and its abundance is a pre-treatment biomarker, KMT2A::EPS15 (MLL-AF1p), t(1;11)(p32;q23) — the infant-ALL cytoplasmic partner, Sequencing-based MRD: better than flow in paediatric B-ALL, and applied to infant KMT2A-rearranged disease exactly once, The near-silent genome of infant KMT2A-r ALL — 1.3 non-silent mutations, and why that is bad news as well as good
264. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34163069
     Phase separation drives aberrant chromatin looping and cancer development

     Ahn JH, Davis ES, Daugird TA, et al. (Wang GG, senior author) · Nature 595(7868):591-595 2021
     used by Condensates in KMT2A-fusion leukemia — an honest verdict: not established for AFF1/AFF4/AF9, load-bearing only in ENL-mutant and NUP98 fusions, Experiment (proposed) — cross-family interface point-mutant panel: is the obligate interface real in each fusion?, Experiment: does KMT2A::AFF1 form condensates at endogenous levels, and does it need them? The separation-of-function and IDR-swap test, Hypothesis: KMT2A::AFF1 does not require phase separation — recruitment biochemistry is sufficient, and the condensate model does not transfer from NUP98/ENL, Mechanism class 1 — chromatin and elongation hijack (KMT2A-r, NUP98-r), Mechanism class 4 — condensate-driven transcriptional rewiring (NUP98-r, EWSR1::FLI1), NUP98 FG condensates, audited assay by assay: no half-bleach has ever been done and no NUP98 fusion has ever been endogenously tagged, NUP98 fusions share the menin dependency (confirmed preclinically) — and the partner-supplied reader/writer module is not why, NUP98::KDM5A (NUP98-JARID1A), t(11;12)(p15;p13), NUP98::NSD1, t(5;11)(q35;p15.5), The nuclear pore and NUP98 fusions — a fusion that takes a pore protein's disordered repeats off the pore and builds nuclear droplets with them, Where KMT2A and its fusions sit inside the nucleus — SNL1/SNL2, nuclear speckles and the condensate question
265. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34706236
     Defining the fetal origin of MLL-AF4 infant leukemia highlights specific fatty acid requirements

     Symeonidou V, Jakobczyk H, Bashanfer S, et al. · Cell Reports 2021
     used by CRISPR-engineered t(4;11) in human fetal liver — the only model that reproduces infant-specific biology, ELOVL1 - the fatty-acid elongase that infant MLL-AF4 ALL retains from its fetal origin, and the lipid enzyme on the opposite side of the divide from ACSL4, Retained fetal programme — the infant-versus-adult stem cell difference, and the reason KMT2A::AFF1 needs no second mutation, The lipid-dependent state — ACSL4 and polyunsaturated fatty acid utilisation in KMT2A-rearranged AML, against ELOVL1 and saturated elongation in KMT2A::AFF1 infant ALL, The myeloid/lymphoid metabolic split in KMT2A-rearranged leukaemia is set by CELL OF ORIGIN (fetal versus adult), not by lineage or by the fusion partner
266. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33135273
     Quantification of NG2-positivity for the precise prediction of KMT2A gene rearrangements in childhood acute leukemia.

     Zerkalenkova E, ..., Popov A · Genes Chromosomes Cancer 2021
     used by CSPG4 / NG2 - the flow-cytometry surrogate for a broken KMT2A, and a direct target gene of the fusion that makes it, NG2 reads the fusion's transcriptional programme, not the DNA lesion - so a menin inhibitor should erase the graph's best diagnostic marker while the rearrangement stays put, What an immunophenotype can and cannot tell you about a genotype - the arithmetic of a surrogate marker, worked on NG2
267. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34638301
     Impact of KMT2A Rearrangement and CSPG4 Expression in Pediatric Acute Myeloid Leukemia.

     Hoffmeister LM, ..., Schneider M · Cancers (Basel) 2021
     used by CSPG4 / NG2 - the flow-cytometry surrogate for a broken KMT2A, and a direct target gene of the fusion that makes it, Does the diagnostic marker survive the drug? Surface NG2, CD133, CD10 and CD33 under menin and DOT1L inhibition, with the rearrangement held fixed, KIT / CD117 - the most myeloid-specific antigen in the lineage-assignment panel, and the mutation that is mutually exclusive with KMT2A rearrangement, NG2 reads the fusion's transcriptional programme, not the DNA lesion - so a menin inhibitor should erase the graph's best diagnostic marker while the rearrangement stays put
268. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33902106
     Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia

     Yankova E, Blackaby W, Albertella M, Rak J, De Braekeleer E, Tsagkogeorga G, Pilka ES, Aspris D, Leggate D, Hendrick AG, Webster NA, Andrews B, Fosbeary R, Guest P, Irigoyen N, Eleftheriou M, Gozdecka M, Dias JML, Bannister AJ, Vick B, Jeremias I, Vassiliou GS, Rausch O, Tzelepis K, Kouzarides T · Nature 2021
     used by CTCF/cohesin boundaries and the HOXA topological domain — the 3D scaffold the fusion program runs on, METTL3 — the m6A writer with a clinical-grade inhibitor, an MLL-rearranged AML mechanism, and a B-lymphoid signal that goes the wrong way, RNA m6A (METTL3/YTHDF/YTHDC1) in KMT2A-rearranged leukemia — the empty cell that turned out not to be empty
269. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34385316
     Biochemical insights into Paf1 complex-induced stimulation of Rad6/Bre1-mediated H2B monoubiquitination.

     · Proc Natl Acad Sci U S A 2021
     used by CTR9 — a PAF1C subunit the field assumes is a fusion partner, with no paper that tested it, RTF1 — the PAF1C subunit the graph was missing, on a complex that does bind the retained KMT2A fragment
270. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34280370
     Dynamics and inhibition of MLL1 CXXC domain on DNA revealed by single-molecule quantification.

     Liang L, Ma K, Wang Z, et al. · Biophys J 2021
     used by CXXC to unmethylated CpG DNA: nine mapped contact residues, and an affinity that spans 44 uM to 33 nM depending on the construct, the DNA and the salt, CXXC-DNA interface of the KMT2A fusion: a validated but hard target, Fractional occupancy needs a free concentration as well as a Kd, and nobody has measured either for a KMT2A fusion, One afternoon of titrations that closes a 1,300-fold question: tagless 1147-1203 against tagless 1147-1244, matched in every other respect, Phase-2 dossier: the CXXC-DNA interface - two structures, a genetically validated requirement, and a selectivity problem that decides everything, The comparison that founded 'the CXXC contact is too weak' puts a 300 mM NaCl protein-DNA measurement against a 50 mM NaCl protein-peptide measurement, The CXXC-DNA affinity is a ten-point ladder from 44 uM to 33 nM, not two numbers 1,300-fold apart, and every step but the last is under 5.5-fold, Two entries record zero chemical matter against the CXXC-DNA interface. There is one: dimethyl fumarate, IC50 about 1 uM, and it is already an approved drug
271. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33408242
     St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem

     McLeod C, Gout AM, Zhou X, et al. · Cancer Discovery 2021
     used by Dataset: St. Jude Cloud - the right cohort for this disease, behind a Data Access Agreement we have not applied for, Sequencing phase 2: the order to do things in, ranked by information per unit cost, St. Jude Cloud and the Pediatric Cancer Genome Project — raw paediatric leukaemia genomes a small lab can get without a collaboration
272. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34876685
     Aberrant chromatin landscape following loss of the H3.3 chaperone Daxx in haematopoietic precursors leads to Pu.1-mediated neutrophilia and inflammation.

     Gerber JP, Russ J, Chandrasekar V, Offermann N, Lee HM, Spear S, Guzzi N, Maida S, Pattabiraman S, Zhang R, Kayvanjoo AH, Datta P, Kasturiarachchi J, Sposito T, Izotova N, Händler K, Adams PD, Marafioti T, Enver T, Wenzel J, Beyer M, Mass E, Bellodi C, Schultze JL, Capasso M, Nimmo R, Salomoni P · Nat Cell Biol 2021
     used by DAXX - the strongest of five selective dependencies among 254 unwritten interactors but it FAILS Bonferroni correction (p=0.0128, rank 4 of 254), and not one paper connects it to this disease
273. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33048000
     The DExD box ATPase DDX55 is recruited to domain IV of the 28S ribosomal RNA by its C-terminal region.

     Choudhury P, Kretschmer J, Hackert P, Bohnsack KE, Bohnsack MT · RNA Biol 2021
     used by DDX55 - a large-subunit rRNA helicase that is nucleolar by imaging and nucleoplasmic by its own founding paper, and the narrowest RBP bait to reach KMT2A after DDX52
274. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 35111761
     Primitive Erythropoiesis in the Mouse is Independent of DOT1L Methyltransferase Activity.

     Malcom CA, Ratri A, Piasecka-Srader J, et al. · Front Cell Dev Biol 2021
     used by Degrade DOT1L, inhibit DOT1L, or leave a dead enzyme in place - run all three against the same cells and the same marrow, DOT1L does things that have nothing to do with methylation - which is why blocking its active site was never going to remove all of it, DOT1L was not refuted - the wrong thing was blocked, at a dose nobody finished escalating, Normal blood needs DOT1L too - lose it in an adult mouse and the marrow fails within weeks
275. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34674229
     Early (< 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

     Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL · Cochrane Database Syst Rev 2021
     used by Dexamethasone - the steroid an infant is actually on for most of the protocol, and the one with a high-certainty neurodevelopmental signal in babies
276. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34329467
     TDRD3 promotes DHX9 chromatin recruitment and R-loop resolution.

     Yuan W, et al. · Nucleic Acids Research 2021
     used by DHX9 / RNA helicase A (Q08211) - the other TDRD3 effector, and it is itself the 3' partner of a leukaemia fusion, TOP3B (O95985) - the only human topoisomerase that works on RNA as well as DNA, delivered to the MYC promoter by an arginine mark, and it has poisons
277. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34148065
     Clinicopathologic and prognostic features of TdT-negative pediatric B-lymphoblastic leukemia.

     Klairmont MM, Zhou Y, Cheng C, Pui CH, Jeha S, Gruber TA, et al. · Mod Pathol 2021
     used by DNTT (TdT) - a real gene the graph calls by its enzyme nickname, and TdT-negativity is 100% KMT2A-rearranged in the largest paediatric series
278. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34449554
     Variable Distribution of DOCK-D Proteins between Cytosol and Nucleoplasm in Cell Lines, Effect of Interleukin-4 on DOCK10 in B-Cell Lymphoid Neoplasms, and Validation of a New DOCK10 Antiserum for Immunofluorescence Studies.

     Ruiz-Lafuente N, Minguela A, Moraleda JM et al · Antibodies (Basel) 2021
     used by DOCK10 (Zizimin-3) - the Cdc42/Rac1 exchange factor fused to KMT2A exon 8 in an undifferentiated pleomorphic sarcoma, and the only one of the seven this graph already held as an H3K79me2-marked gene
279. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34320268
     SET-NUP214 and MLL cooperatively regulate the promoter activity of the HoxA10 gene.

     Cigdem S, Saito S, Nishikata D, et al. · Genes to Cells 2021
     used by Does KMT2A::AFF1 bind the histone chaperone SET/TAF-I beta, and does that contact overlap the menin-binding motifs? A co-IP and a peptide competition, Hypothesis: SET::NUP214 activates HOXA partly through recruited wild-type MLL1, which would make a KMT2A-unrearranged leukaemia menin-inhibitor-sensitive, SET / TAF-I beta - a histone chaperone that binds the retained N-terminus of MLL, co-activates HOXA with it, and is itself a HOXA-activating fusion partner that recruits DOT1L, SET / TAF-Ibeta domain map (Q01105, 290 aa) - dimerisation, earmuff, and the acidic tail that binds MLL, SET::NUP214 (TAF-Ibeta-NUP214, SET-CAN), cryptic del(9)(q34.11q34.13) - a HOXA-driving fusion of a histone chaperone to a nucleoporin, with no KMT2A and no menin-binding motif, SET::NUP214 is KMT2A-free in its sequence but not in its mechanism: it binds and condenses wild-type MLL1, which reopens the menin question this beat was sent to close, The CRM1 address is not a menin-free address: NPM1c reaches HOXA the same way and NPM1c AML is menin-inhibitor-sensitive in the clinic
280. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34233157
     Targeted protein degradation reveals a direct role of SPT6 in RNAPII elongation and termination.

     Narain A, Bhandare P, Adhikari B, et al. · Molecular Cell 2021
     used by Does KMT2A::AFF1 change histone turnover at its target genes, or does it read a chromatin state it did not make?, Is any histone chaperone selectively required in KMT2A-rearranged leukaemia? Twenty-nine genes, lineage-split - and the answer is no, with one number worth a null and a positive tail nobody expected, SUPT6H (SPT6) - the histone chaperone that rides with RNA polymerase II, which puts it closer to the fusion's proposed mechanism than anything else in this beat
281. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32242051
     H3K79me2/3 controls enhancer-promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells.

     Godfrey L, ..., Milne TA · Leukemia 2021
     used by Does the diagnostic marker survive the drug? Surface NG2, CD133, CD10 and CD33 under menin and DOT1L inhibition, with the rearrangement held fixed, Enhancer usage in KMT2A-rearranged leukemia — occupancy and amplification, not hijacking, and not super-enhancers, Enhancer-promoter contacts at KMT2A-fusion target loci — what the fusion uses, what it does not, and what survives the drug, Polycomb in KMT2A-r leukemia — core PRC2 required, EZH2 and BMI1 dispensable, and CBX8 acting outside its repressive role, PROM1 / CD133 - a direct MLL-AF4 target switched on by an intragenic H3K79me2/3 enhancer, and the one surface target in this disease with a published human-relevant kill, Step 5 — The output program: HOXA9/HOXA10/MEIS1/PBX3 plus MEF2C, MYB, BCL2, FLT3 and PROM1/CD133, Thomas Milne (MRC WIMM, Oxford) — MLL-AF4 target biology, enhancer architecture and PROM1/CD133
282. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34187895
     DOT1L complex regulates transcriptional initiation in human erythroleukemic cells

     Wu A, Zhi J, Tian T, et al. · Proc Natl Acad Sci U S A 2021
     used by DOT1L is widely framed as a transcription-elongation factor, but the one direct test found in erythroleukaemic cells reported a role in initiation - in a non-KMT2A-rearranged line, so it is a counter-lead for the elongation model, not a refutation
283. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34568318
     MCL-1 Inhibition Overcomes Anti-apoptotic Adaptation to Targeted Therapies in B-Cell Precursor Acute Lymphoblastic Leukemia

     Manzano-Munoz A, Alcon C, Menendez P, Ramirez M, Seyfried F, Debatin KM, et al., Montero J · Front Cell Dev Biol 2021
     used by Dynamic BH3 profiling before and after menin inhibition — a one-week assay on primary cells that would choose the BH3-mimetic partner, and has never been run in lymphoid disease, The apoptotic priming state — KMT2A-rearranged infant ALL is the one childhood ALL subgroup that is BCL-2-dependent rather than BCL-XL-co-dependent, and BH3 profiling is how that was measured
284. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34265249
     Allosteric transcription stimulation by RNA polymerase II super elongation complex

     Chen Y, Vos SM, Dienemann C, Ninov M, Urlaub H, Cramer P · Molecular Cell 81(16):3386-3399.e10 2021
     used by EAF1 — the interactor with an actual subnuclear phenotype: an MLL fusion evicts it from Cajal bodies, and the bodies themselves fall apart, ELL — rank 7 on selectivity and the deepest common-essential in the top ten, with one NMR fragment to its name, SUPT5H (SPT5) — the pausing factor the KMT2A field has never studied, and the counted absence that undercuts 'the fusion hijacks pause release', The ELL/EAF activation module (ELL2, EAF1, EAF2) — a general elongation stimulator, not a KMT2A-fusion dependency
285. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34586829
     A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models.

     Yu X, Li D, Kottur J, Shen Y, Kim HS, Park KS, Tsai YH, Gong W, Wang J, Suzuki K, Parker J, Herring L, Kaniskan HU, Cai L, Jain R, Liu J, Aggarwal AK, Wang GG, Jin J · Sci Transl Med 2021
     used by Eleven abstract-level bounded absences re-tested with the instrument that overturned the HDAC6 one - ten survive, one is not checkable this way, none overturned, Four hours of MS67 in MV4;11, two KMT2A antibodies: the cheapest test of whether WRAD reaches the fusion or only wild-type KMT2A, Four ways a WDR5 result can be true and have nothing to do with KMT2A, The WRAD degron absence survives, and the reason is worth more than the verdict: a 3.7 nM chemical degron of WDR5 with 2-hour kinetics already exists IN MV4;11, and it still cannot see the fusion
286. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34431785
     HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis.

     Takahashi S, Kanai A, et al. · eLife 2021
     used by ELL has never been placed in a cell state — its entire leukaemia state literature is its own fusion transcript used as a residual-disease marker, JADE3 / PHF16 (Q92613) - the HBO1-complex scaffold with the strongest pan-fusion evidence in this beat, and an independent published contact with MLL, KMT2A::AFF1 retains THD2 by position, so the HBO1 contact can apply to it — but the paper that established that contact tested MLL-ELL, MLL-AF6 and MLL-AF10, never the index fusion
287. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33334895
     Elongin A associates with actively transcribed genes and modulates enhancer RNA levels with limited impact on transcription elongation rate in vivo.

     Ardehali MB, Damle M, Perea-Resa C, Blower MD, Kingston RE · J Biol Chem 2021
     used by ELOA / TCEB3, Elongin A (Q14241) - a Pol II elongation factor in the pan-MLL-fusion core, ALONE, with none of its own complex and a non-zero negative control
288. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33507234
     Loss of tRNA-modifying enzyme Elp3 activates a p53-dependent antitumor checkpoint in hematopoiesis.

     Rosu A, El Hachem N, et al. · J Exp Med 2021
     used by ELP3 - the catalytic subunit, the only Elongator protein with a real acetyltransferase domain, and the one whose loss in mouse blood causes marrow failure and then p53-mutant leukaemia, ELP5 (DERP6) - the bridge that joins ELP3 to ELP4, the most essential Elongator subunit in DepMap, and a gene whose cytoplasmic call rests on an overexpression experiment
289. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33893150
     Transcriptional Silencing of ALDH2 Confers a Dependency on Fanconi Anemia Proteins in Acute Myeloid Leukemia.

     Yang Z, Wu XS, et al. · Cancer Discov 2021
     used by Endogenous aldehydes and silenced ALDH2 — the rival explanation for an FA dependency in acute leukaemia, and the only one with an experiment behind it, FAAP100 — FA core complex; rank 36 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all, FANCL — FA core complex; rank 26 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all, KMT2A rearrangement creates a requirement for the FA ubiquitin-transfer module — the claim, its prior, and the four results that would kill it, Measure replication stress directly in KMT2A-rearranged cells instead of inferring it from a dependency ranking, The FA core complex does not move together, and that is the strongest argument against reading this as a Fanconi-pathway dependency at all, The Fanconi signal is in both lineage halves, survives the correlation-proof null, and is still there when lineage is held constant, Transcription–replication conflict as the candidate reason KMT2A-rearranged cells need the Fanconi pathway — a chain with two measured links and three inferred ones, UBE2T — E2; rank 33 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
290. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33431820
     BET inhibition disrupts transcription but retains enhancer-promoter contact

     Crump NT, Ballabio E, Godfrey L, Thorne R, Repapi E, Kerry J, Tapia M, Hua P, Lagerholm C, Filippakopoulos P, Davies JOJ, Milne TA · Nature Communications 2021
     used by Enhancer-promoter contacts at KMT2A-fusion target loci — what the fusion uses, what it does not, and what survives the drug
291. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33301426
     Bone marrow niche ATP levels determine leukemia-initiating cell activity via P2X7 in leukemic models

     He X, Wan J, Yang X, Zhang X, Huang D, Li X, Zou Y, Chen C, et al. · Journal of Clinical Investigation 2021
     used by Every niche-disrupting drug strips the patient's own stem cells of the same shelter — the bite-back that applies to the whole beat, The endosteal niche — the bone surface, where leukaemia-initiating cells were imaged homing and dividing symmetrically
292. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34529760
     A novel class of ZNF384 aberrations in acute leukemia.

     Zaliova M, Winkowska L, Stuchly J, Fiser K, Triska P, Zwyrtkova M, Hrusak O, Starkova J, Sramkova L, Stary J, Trka J, Zuna J · Blood Adv 2021
     used by Express a partner-free ZNF384 C-terminal truncation in HSPCs alongside TCF3::ZNF384 - the one experiment that decides whether the fusion partner is necessary, Four sources give ZNF384 three different zinc-finger counts - 8, 6 and 'five to eight' - and the paralogue's feature table explains where the 6 comes from, How common is ZNF384-rearranged leukaemia? Published answers span 1.6% to about 20% and the spread is almost entirely denominator, not biology, Last-exon indels that truncate the ZNF384 C-terminus phenocopy the fusion - so the fusion partner may not be the necessary element, The necessary lesion in ZNF384-rearranged leukaemia is LOSS of the ZNF384 C-terminus, not GAIN of a fusion partner, The ZNF384 family is not the inverse of KMT2A::AFF1 - it is the SAME grammar written in the opposite gene order, and three of the four claims in the inverse framing are false, ZNF362 - the paralogue that makes the same leukaemia with the same partners, and that explains the six-zinc-finger convention, ZNF384::TEX41 - the case that breaks the family's architecture: ZNF384 is the 5' partner, the 3' partner is a lncRNA, and the fusion is out of frame
293. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33514705
     Structures of monomeric and dimeric PRC2:EZH1 reveal flexible modules involved in chromatin compaction.

     Grau D, Zhang Y, Lee CH, Valencia-Sánchez M, Zhang J, Wang M, et al. · Nat Commun 2021
     used by EZH1 - the paralogue that makes the approved EZH2 drug the wrong drug for this disease, PRC2 - the complex, not the subunit, is the unit every experiment in this disease actually resolves
294. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33479542
     Biomolecular condensation of NUP98 fusion proteins drives leukemogenic gene expression

     Terlecki-Zaniewicz S, et al. · Nature Structural & Molecular Biology 28(2):190-201 2021
     used by Five KMT2A-free NUP98 fusions bind MLL1 and the NSL complex — and one unbiased mass-spectrometry study failed to reproduce it, NUP98 FG condensates, audited assay by assay: no half-bleach has ever been done and no NUP98 fusion has ever been endogenously tagged, NUP98::DDX10, inv(11)(p15q22) — the 'helicase' fusion whose helicase activity turns out not to be the point, NUP98::KDM5A (NUP98-JARID1A), t(11;12)(p15;p13), NUP98::NSD1, t(5;11)(q35;p15.5)
295. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34811450
     FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells.

     Yamawaki K, Shiina I, Murata T, Tateyama S, Maekawa Y, Niwa M, Shimonaka M, Okamoto K, Suzuki T, Nishida T, Abe R, Obata Y · Sci Rep 2021
     used by FLT3-ITD signals from inside the cell, not from the surface - and whether it is the ER or the Golgi decides which pathway fires
296. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 34956984
     Total Body Irradiation Forever? Optimising Chemotherapeutic Options for Irradiation-Free Conditioning for Paediatric Acute Lymphoblastic Leukaemia.

     Ben Hassine K, Powys M, Svec P, Pozdechova M, Versluys B, Ansari M, Shaw PJ · Frontiers in Pediatrics 2021
     used by Fludarabine - the immunosuppressive half of modern conditioning, given as a phosphate prodrug, cleared by the kidney, and dosed by a body-surface-area rule that measurably fails in children, Total body irradiation and the age-four boundary - the best conditioning in childhood ALL has never been tested in the children who most need a transplant, Treosulfan - a European conditioning standard for three decades that the FDA first approved in January 2025, for a diagnosis and an age that exclude the infant with KMT2A-rearranged ALL
297. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34551306
     Enhancer recruitment of transcription repressors RUNX1 and TLE3 by mis-expressed FOXC1 blocks differentiation in acute myeloid leukemia

     Simeoni F, Romero-Camarero I, Camera F, Amaral FMR, Sinclair OJ, Papachristou EK, Spencer GJ, Lie-A-Ling M, et al. · Cell Reports 36:109725 2021
     used by FOXC1 - a mesenchymal forkhead factor derepressed in HOXA-high AML that blocks monocytic differentiation, with a real mechanism and zero published connection to KMT2A rearrangement
298. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 35087776
     Aberrant GATA2 Activation in Pediatric B-Cell Acute Lymphoblastic Leukemia

     Wang H, Cui B, Sun H, Zhang F, Rao J, Wang R, Zhao S, Shen S, et al. · Frontiers in Pediatrics 9:795529 2021
     used by GATA2 - the least KMT2A-selective gene on this beat, ranking 17,591 of 17,728, and a factor whose leukaemia biology is about stemness and chemoresistance rather than about the fusion, GATA2 outlier activation in KMT2A::USP2 B-ALL - the only transcriptional output ever measured for this fusion
299. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33933995
     G-patch domain-containing protein 4 localizes to both the nucleoli and Cajal bodies and regulates cell growth and nucleolar structure.

     Hirawake-Mogi H, Thanh Nhan NT, Okuwaki M · Biochem Biophys Res Commun 2021
     used by GPATCH4 (Q5T3I0) - a nucleolar and Cajal-body helicase cofactor in the pan-MLL-fusion core, with no DHX15 and no G-patch relative beside it
300. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33139925
     Gephyrin-mediated formation of inhibitory postsynaptic density sheet via phase separation.

     Bai G, Wang Y, Zhang M · Cell Res 2021
     used by GPHN (gephyrin) — synaptic scaffold and molybdenum-cofactor enzyme, KMT2A fusion partner in t(11;14)(q23;q24)
301. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     NCBI GEO samples GSM4133857-GSM4133860, series GSE139196: 'ChIP on SUV39H1 (KMT1A) ... of MCF-7 cells', chip antibody: SUV39H1 (KMT1A), library strategy ChIP-Seq

     · NCBI Gene Expression Omnibus 2021
     used by GSE139196: SUV39H1 ChIP-Seq in MCF-7 with and without 40 minutes of estradiol - a ligand-inducible SUV39H1 occupancy experiment, filed under the retired symbol KMT1A in its own sample titles
302. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33803739
     Induction of AML Preleukemic Fusion Genes in HSPCs and DNA Damage Response in Preleukemic Fusion Gene Positive Samples.

     Kosik P, Durdik M, Skorvaga M, Klimova D, Kochanova D, Cerna Z, et al. · Antioxidants (Basel) 2021
     used by H2AX - filed as a gene and not as a mark, and the reason that decision changes what the graph can say, Hypothesis: what breaks KMT2A in a fetus is TOP2B doing its normal transcription-coupled job in a non-cycling progenitor, with no poison involved and repair capacity as the rate-limiting variable, TP53BP1 (53BP1) - the end-protection factor that decides between the two repair routes, reachable only under the wrong symbol
303. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33618250
     Discovery of higenamine as a potent, selective and cellular active natural LSD1 inhibitor for MLL-rearranged leukemia therapy.

     Fang Y; Yang C; Teng D; Su S; Luo X; Liu Z; et al. · Bioorg Chem 2021
     used by H3K4me2 - the LSD1 substrate, and the only histone mark ever compared head-to-head between two KMT2A fusion partners in human cells
304. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34185806
     Comparative distributions of RSBN1 and methylated histone H4 Lysine 20 in the mouse spermatogenesis.

     Wang Y, et al. · PLoS One 2021
     used by H4K20me2 - the abundant repair-linked H4 mark, the 53BP1 docking site, and the first H4K20 state in this graph; never once measured in a KMT2A-rearranged cell, RSBN1 / KDM9 (Q5VWQ0) - an H4K20me2/me3 demethylase in the AFF4 proximity record, and the only read-queue partner that is a chromatin enzyme at all
305. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33420489
     The T-box transcription factor Eomesodermin governs haemogenic competence of yolk sac mesodermal progenitors

     Harland LTG, Simon CS, Senft AD, Costello I, Greder L, Imaz-Rosshandler I, Göttgens B, Marioni JC, Bikoff EK, Porcher C, de Bruijn MFTR, Robertson EJ · Nature Cell Biology 2021
     used by Haemogenic endothelium — the vessel-wall cell that gives birth to blood
306. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34036344
     Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency.

     Wang Y, Li W, Schulz VP, Zhao H, Qu X, Qi Q, Cheng Y, Guo X, Zhang S, Wei X, Liu D, Yazdanbakhsh K, Hillyer CD, Mohandas N, Chen L, Gallagher PG, An X · Blood 2021
     used by HDAC5 - the eraser in an existing entry's own id, and the one HDAC in this graph that erases a mark on a fusion partner protein rather than on a histone
307. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 33262526
     HDAC7 is a major contributor in the pathogenesis of infant t(4;11) proB acute lymphoblastic leukemia.

     de Barrios O, Galaras A, Trincado JL, Azagra A, Collazo O, Meler A, Agraz-Doblas A, Bueno C, Ballerini P, Cazzaniga G, Stam RW, Varela I, De Lorenzo P, Valsecchi MG, Hatzis P, Menéndez P, Parra M · Leukemia 2021
     used by HDAC7 - the eraser the index fusion silences, where the proposed therapy is to INDUCE the HDAC, and two 2024-2025 papers point in opposite directions
308. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33477970
     Unlike Its Paralog LEDGF/p75, HRP-2 Is Dispensable for MLL-R Leukemogenesis but Important for Leukemic Cell Survival.

     Van Belle S, El Ashkar S, Cermakova K, et al. · Cells 2021
     used by HDGF - the third PWWP paralogue, which pulls down LEDGF but has the reader domain WITHOUT the domain that grips MLL, HDGFL2 / HRP-2 - the second IBD protein, which binds KMT2A at the same site with the same affinity and does NOT need menin to do it, LEDGF PWWP chemistry exists after all - 68 fragment hits, double-digit micromolar leads - and the pocket has a structural ceiling the NSD PWWPs do not, None of the five selective unwritten interactors survives a null, and FANCD2 - the one that carried a story - is the second weakest of them at p = 0.12, The paralogue that covers for LEDGF: HRP-2 carries the only other IBD in the human proteome, substitutes for LEDGF in HIV integration, and the double knockout is embryonic lethal
309. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34415726
     A Peptidomimetic Ligand Targeting the Chromodomain of MPP8 Reveals HRP2's Association with the HUSH Complex.

     Waybright JM, et al. · ACS Chem Biol 2021;16:1721-1736 2021
     used by HDGFL2 / HRP-2 - the second IBD protein, which binds KMT2A at the same site with the same affinity and does NOT need menin to do it
310. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34242617
     The histone H3.3 chaperone HIRA restrains erythroid-biased differentiation of adult hematopoietic stem cells.

     Murdaugh RL, Hoegenauer KA, Kitano A, et al. · Stem Cell Reports 2021
     used by HIRA - the chaperone that puts new H3.3 into transcribed gene bodies, and therefore the machine that runs this graph's clearance clock
311. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 34262023
     The long noncoding RNA HOTAIRM1 controlled by AML1 enhances glucocorticoid resistance by activating RHOA/ROCK1 pathway through suppressing ARHGAP18

     Liang L, Gu W, Li M, Gao R, Zhang X, Guo C, Mi S · Cell Death & Disease 12(7):702 2021
     used by HOTAIRM1 lncRNA — the myeloid-differentiation transcript at the 3' end of HOXA, with a KMT2A-r evidence gap
312. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 33754013
     Comprehensive investigation of the clinical significance of long non-coding RNA HOXA-AS2 in acute myeloid leukemia using genome-wide RNA sequencing dataset

     Huang R, Liao X, Wang X, Li Q · Journal of Cancer 12(7):2151-2164 2021
     used by HOXA-AS2 and HOXA-AS3 — mid-cluster antisense transcripts with essentially no KMT2A-r evidence
313. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34111240
     miR-130b and miR-128a are essential lineage-specific codrivers of t(4;11) MLL-AF4 acute leukemia

     Malouf C, Antunes ETB, O'Dwyer M, Jakobczyk H, Sahm F, Landua SL, Anderson RA, Soufi A, Halsey C, Ottersbach K · Blood 2021
     used by Hypothesis: releasing the KMT2A::AFF1 differentiation block sends cells toward myeloid, not mature B, in a measurable fraction of infant cases, Lymphoid-primed multipotent progenitor (LMPP) — the bi-potent cell that explains how one fusion makes two lineages, Pro-B cell — the stage at which KMT2A::AFF1 leukaemia is arrested, and the phenotype the diagnosis is made on, The primed chromatin state — what is actually established, and why the word 'bivalent' should be used carefully here, The pro-B arrest state — what a KMT2A::AFF1 blast is actually doing while it sits there, The stem-like self-renewal state — a limited stem-cell module grafted onto a committed cell
314. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33203699
     Decitabine Induces Gene Derepression on Monosomic Chromosomes: In Vitro and In Vivo Effects in Adverse-Risk Cytogenetics AML

     Greve G, Schüler J, Grüning BA, Berberich B, Stomper J, Zimmer D, Gutenkunst L, Bönisch U, Meier R, Blagitko-Dorfs N, Grishina O, Pfeifer D, Weichenhan D, Plass C, Lübbert M · Cancer Research 2021
     used by Hypothesis: t(4;11) infant ALL is a hypermethylated genome whose transposable elements can be reawakened, and that reawakening is an untested immunotherapeutic lever
315. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34140467
     Poltheta inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance

     Zatreanu D, Robinson HMR, Alkhatib O, et al. · Nature communications 2021
     used by Hypothesis: the KMT2A break can be prevented rather than the fusion treated - stated so it can be killed, and it probably should be, Which repair pathway glues the fusion together: classical NHEJ vs alternative end joining
316. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34916496
     R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability

     Mosler T, Conte F, Longo GMC, Mikicic I, Kreim N, Möckel MM, Petrosino G, Flach J, Barau J, Luke B, Roukos V, Beli P · Nature Communications 2021
     used by Hypothesis: the R-loop landscape of a KMT2A::AFF1 blast is remodelled by the fusion and is both a vulnerability and a source of ongoing genome instability
317. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33805930
     IGF2BP3 Associates with Proliferative Phenotype and Prognostic Features in B-Cell Acute Lymphoblastic Leukemia

     · Cancers 2021
     used by IGF2BP3 — an RNA-binding protein required for MLL-Af4 leukaemogenesis in mice that CRISPR barely touches in human lines, IGF2BP3 marks the fetal programme AND is required for B-ALL survival - the trap is not expression-for-requirement, it is requirement-for-state-maintenance, RNA-binding proteins set how much KMT2A::AFF1 protein a cell makes from its own fusion transcript, The decisive experiment: acute degron removal of IGF2BP3, IGF2BP2 and both, read on self-renewal and xenograft initiation rather than bulk dropout
318. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34793513
     A B-cell developmental gene regulatory network is activated in infant AML.

     Bolouri H, Ries R, et al. · PloS one 2021
     used by IGF2BP3 marks the fetal programme AND is required for B-ALL survival - the trap is not expression-for-requirement, it is requirement-for-state-maintenance, let-7 microRNA family (12 HGNC loci) - the effector LIN28B blocks. CORRECTED IN-SESSION: the headline 'zero papers in KMT2A leukaemia' was a NAME-LIST ARTEFACT; searching MLL instead of KMT2A returns three, one of them directly on point, LIN28B and IGF2BP3 are co-regulated members of ONE onco-fetal module in infant leukaemia - which strengthens the graph's existing scepticism about IGF2BP3 rather than weakening it
319. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33197925
     CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells.

     Surka C, Jin L, Mbong N, et al. (29 authors; senior author Lu G) · Blood 2021
     used by ILF3 / NF90 - a nucleolar dsRNA-binding coactivator whose chromatin residency was mapped in the same leukaemia line that proximity-labelled KMT2A
320. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34446068
     MEN1 silencing aggravates tumorigenic potential of AR-independent prostate cancer cells through nuclear translocation and activation of JunD and β-catenin.

     Luo Y, Vlaeminck-Guillem V, Baron S, Dallel S, Zhang CX, Le Romancer M · J Exp Clin Cancer Res 2021
     used by JUND - the AP-1 subunit menin holds down, and the one a menin inhibitor lets go
321. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34362741
     Differential H4K16ac levels ensure a balance between quiescence and activation in hematopoietic stem cells.

     Pessoa Rodrigues C, Akhtar A · Sci Adv 2021
     used by KANSL1 - the NSL scaffold, and the protein through which WDR5 binding to NSL and to MLL/COMPASS is mutually exclusive, KAT8/MOF sets the quiescence set-point of the blood stem cell - and its catalytic activity is separately required for MLL-AF9 leukaemia, which DepMap also cannot see
322. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33657400
     Complex-dependent histone acetyltransferase activity of KAT8 determines its role in transcription and cellular homeostasis.

     Radzisheuskaya A, Shliaha PV, Grinev VV, Shlyueva D, Damhofer H, Koche R, Gorshkov V, Kovalchuk S, Zhan Y, Rodriguez KL, Johnstone AL, Keogh MC · Mol Cell 2021
     used by KAT8/MOF is not only a chromatin enzyme: a measured mitochondrial pool binds mtDNA, and the chromatin address depends on which complex it is in
323. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34526716
     UTX condensation underlies its tumour-suppressive activity.

     Shi B; Li W; Song Y; Wang Z; Ju R; Ulman A; Hu J; Palomba F; Zhao Y; Le JP; Jarrard W; Dimoff D; Digman MA; Gratton E; Zang C; Jiang H · Nature 2021
     used by KDM6A / UTX — a commonly asserted KMT2A partner that belongs to a different complex and points the opposite way
324. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33647817
     Expression of a novel type of KMT2A/EPS15 fusion transcript in FLT3 mutation-positive B-lymphoblastic leukemia with t(1;11)(p32;q23).

     Yamamoto K, Yakushijin K, Mizutani Y, Okuni-Watanabe M, Goto H, Higashime A, et al. · Cancer Genet 2021
     used by KMT2A::EPS15 (MLL-AF1p), t(1;11)(p32;q23) — the infant-ALL cytoplasmic partner
325. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 35004749
     MLL-SEPT5 Fusion Transcript in Myelodysplastic Syndrome Patient With t(11;22)(q23;q11).

     Zou D, Chen Y, Wu N, et al. · Front Med (Lausanne) 2021
     used by KMT2A::SEPTIN5 (MLL-SEPT5 / MLL-hCDCrel-1), t(11;22)(q23;q11.2)
326. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32984885
     Monocytic Acute Myeloid Leukemias with KM2TA Translocations to Chromosome 17q that May Clinically Mimic Acute Promyelocytic Leukemia.

     Balbuena-Merle RI, Tormey CA, DiAdamo A, et al. · Lab Med 2021
     used by KMT2A::SEPTIN9 (MLL-SEPT9 / MLL-MSF), t(11;17)(q23;q25)
327. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 34440566
     Structure, Activity and Function of the MLL2 (KMT2B) Protein Lysine Methyltransferase.

     Klonou A, Chlamydas S, Piperi C · Life (Basel) 2021
     used by KMT2B (MLL2/MLL4) - the other protein menin binds, and the one this graph never wrote
328. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33596429
     Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy.

     Chen R, Okeyo-Owuor T, Patel RM, et al. · Cell Rep 2021
     used by KMT2C (MLL3) - the fetal brake on MLL-rearranged leukaemia, and a 7q tumour suppressor chemotherapy selects against, KMT2D (MLL2/MLL4) - the gene named in this graph's menin-resistance entry, written here for the first time, The MLL3/4-UTX switch fails to throw — menin inhibition kills by turning something ON, and cells that cannot turn it on survive
329. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34070855
     LEDGF/p75 Is Required for an Efficient DNA Damage Response.

     Liedtke V, Schröder C, et al. · Int J Mol Sci 2021
     used by LEDGF as a survival factor rather than a tether: it is upregulated in chemoresistant AML blasts, protects against daunorubicin, and knocking it down sensitises MLLr lines, PSIP1 makes two proteins and only one of them has the IBD: a p52 result is not a p75 result, and the knockout mouse removes both, The bite-back surface: LEDGF tethers CtIP to active chromatin and is required for DNA-end resection and homologous recombination
330. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32646889
     DUX4r, ZNF384r and PAX5-P80R mutated B-cell precursor acute lymphoblastic leukemia frequently undergo monocytic switch

     Novakova M, Zaliova M, Fiser K, Vakrmanova B, Slamova L, et al. · Haematologica 2021
     used by Lineage switch as antigen escape from CD19-directed therapy in KMT2A-rearranged leukemia, Lineage switch in KMT2A-rearranged leukemia — the same clone changes what kind of blood cell it is
331. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33542097
     Mediator subunit MED1 is required for E2A-PBX1-mediated oncogenic transcription and leukemic cell growth.

     Lee YL, Ito K, Pi WC, Lin IH, Chu CS, Malik S, Cheng IH, Chen WY, Roeder RG · Proc Natl Acad Sci U S A 2021
     used by MED26 — a common-essential Mediator subunit with a solved 87-residue domain and no ChEMBL target entity at all
332. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 33833382
     Can we prevent childhood Leukaemia?

     Greaves M, Cazzaniga V, Ford A · Leukemia 2021
     used by Mel Greaves (Centre for Evolution and Cancer, ICR London) — natural history, in-utero origin and the prevention question
333. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34500465
     Hematopoietic stem cell transplantation for infants with high-risk KMT2A gene-rearranged acute lymphoblastic leukemia

     Takachi T, Watanabe T, Miyamura T, Moriya Saito A, Deguchi T, Hori T, Yamada T, Ohmori S, et al. · Blood Advances 2021
     used by Melphalan - the third agent in Interfant-06 conditioning, dosed per square metre in babies who are dosed per kilogram for everything else in the same week, Who gets transplanted in infant KMT2A-rearranged ALL, and whether it helps - four criteria, and a literature that points both ways
334. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31649131
     EVI1 triggers metabolic reprogramming associated with leukemogenesis and increases sensitivity to L-asparaginase.

     Saito Y, et al. · Haematologica 2021
     used by Menin inhibition collapses the serine/one-carbon/ASNS programme in KMT2A::AFF1 cells - PHGDH -3.24, PSAT1 -2.40, ASNS -1.72, flat in a wild-type line - so it should re-sensitise KMT2A-rearranged ALL to asparaginase, a combination PubMed has zero records for
335. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 34939756
     Induction of Beta Cell Replication by Small Molecule-Mediated Menin Inhibition and Combined PKC Activation and TGF-beta Inhibition as Revealed by A Refined Primary Culture Screening.

     Pahlavanneshan S, Behmanesh M, Tahamtani Y, Hajizadeh-Saffar E, Basiri M, Baharvand H · Cell Journal 2021
     used by Menin inhibition makes adult human beta cells divide in a dish - the hardest thing in beta-cell biology
336. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 34251718
     Leukemogenesis via aberrant self-renewal by the MLL/AEP-mediated transcriptional activation system

     Yokoyama A · Cancer Science 2021
     used by Michael Cleary (Stanford) & Akihiko Yokoyama (National Cancer Center, Tsuruoka) — the groups that discovered the menin requirement itself
337. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33718232
     Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia

     Brethon B, Lainey E, Caye-Eude A, et al. · Frontiers in Oncology 2021
     used by Mixed phenotype acute leukaemia (MPAL) and acute leukaemia of ambiguous lineage, Two clones, two antibodies: a four-month-old with refractory KMT2A::AFF1 mixed-phenotype leukaemia treated with blinatumomab and gemtuzumab together
338. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     PDB entries 5DAG (Crystal structure of PZP domain of human AF10 protein) and 7MJU (Crystal structure of human AF10 PZP bound to histone H3 tail), with UniProt P55197 chain mappings

     RCSB Protein Data Bank; UniProt Consortium · RCSB Protein Data Bank 2021
     used by MLLT10 / AF10 — domain architecture and residue coordinates
339. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34073699
     Classification of Monocytes, Promonocytes and Monoblasts Using Deep Neural Network Models: An Area of Unmet Need in Diagnostic Hematopathology

     Osman M, Akkus Z, Jevremovic D, Nguyen PL, Roh D, Al-Kali A, et al., Salama ME · Journal of Clinical Medicine 2021
     used by Monoblast — the immature monocyte that names FAB M5a, the dominant morphology of congenital KMT2A leukaemia
340. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34819355
     Distinct histone H3-H4 binding modes of sNASP reveal the basis for cooperation and competition of histone chaperones.

     Liu CP, Jin W, Hu J, et al. · Genes & Development 2021
     used by NASP - the soluble histone reservoir, and the only gene in this beat with a real selective difference at a pan-essentiality shallow enough to interpret
341. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34354240
     The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(6;11).

     Kundu A, Kowarz E, Marschalek R · Oncogene 2021
     used by Nobody has ever stratified any KMT2A::MLLT1 outcome or drug-response analysis by reciprocal or spliced status - a measured absence, with the queries, Six relapses and a change of lineage: KMT2A::AFDN T-lymphoblastic lymphoma that came back as monoblastic leukaemia, and a seventh remission that held, t(6;11) makes four fusion genes, not two, and the PHD/bromodomain cassette is what opens chromatin in all of them
342. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33446254
     SPIN reveals genome-wide landscape of nuclear compartmentalization

     Wang Y, Zhang Y, Zhang R, van Schaik T, Zhang L, Sasaki T, Peric-Hupkes D, Chen Y, Gilbert DM, van Steensel B, Belmont AS, Ma J · Genome Biology 2021
     used by Nuclear speckles — the compartment everyone assumes KMT2A::AFF1 uses, on evidence that skips AFF1 itself
343. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33823140
     p53 mediates target gene association with nuclear speckles for amplified RNA expression

     Alexander KA, Coté A, Nguyen SC, et al. · Molecular Cell 2021
     used by Nuclear speckles — the compartment everyone assumes KMT2A::AFF1 uses, on evidence that skips AFF1 itself
344. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34383740
     Sharma et al. - NUP98 fusion methods describing 'NUP98 dCT (amino acids 1-469)'

     · PLoS Genetics 2021
     used by NUP98 fusions retain a 469-residue FG repeat region that carries ZERO annotated modification sites - the cleanest retained-portion PTM absence in the four fusion families checked
345. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32381579
     The clinical and biological characteristics of NUP98-KDM5A in pediatric acute myeloid leukemia

     Noort S, et al. · Haematologica 106(2):630-634 2021
     used by NUP98 rearrangements are 7.2% of paediatric AML and 1.6% of adult, with 35% five-year overall survival — and the partner changes everything
346. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34448811
     KDM5A suppresses PML-RARα target gene expression and APL differentiation through repressing H3K4me2.

     Xu S, Wang S, Xing S, et al. · Blood Advances 2021
     used by Outside ENCODE the resection layer is not one absence but four: 31 BRCA1, 45 CBX3, 22 KDM5A, 14 MRE11 and 8 CtIP ChIP-seq experiments exist in ChIP-Atlas, DNA2 and RAD50 have one each, and only BARD1 and EXO1 have none in any of the three archives
347. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34083515
     A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival.

     Massett ME, Monaghan L, et al. · Cell death & disease 2021
     used by PAF1c is needed by the normal stem cell and by the leukaemia, and the genes it regulates in each are different
348. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 32996365
     MiR-181a enhances drug sensitivity of mixed lineage leukemia-rearranged acute myeloid leukemia by increasing poly(ADP-ribose) polymerase1 acetylation.

     · PubMed record 2021
     used by PARP1 - the target whose inhibitors this disease was specifically shown to resist, and which three later papers combine anyway
349. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33937032
     Preclinical Evaluation of Carfilzomib for Infant KMT2A-Rearranged Acute Lymphoblastic Leukemia

     Cheung LC, de Kraa R, Oommen J, et al. · Frontiers in Oncology 2021
     used by PER-485 (CVCL_W984) — the relapse half of a matched infant t(4;11) pair, and it has lost CD19, PER-490 (CVCL_W986) — a KMT2A::AFF1 B-ALL line from a nine-day-old infant, PER-494 (CVCL_A8JU) — infant t(4;11;7) line, and the one whose AFF1 was never demonstrated, PER-785 (CVCL_IZ03) — infant t(4;11) line from a child who survived, Verdict: 'eleven cell lines, none infant-derived' is right about the screen and wrong about the material — at least ten infant KMT2A::AFF1 lines exist
350. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33436370
     Serine Biosynthesis Is a Metabolic Vulnerability in FLT3-ITD-Driven Acute Myeloid Leukemia.

     Bjelosevic S, Gruber E, Newbold A, et al., Johnstone RW · Cancer Discov 2021
     used by PHGDH (O43175) - the largest menin-SELECTIVE fall in the whole serine panel, and the least essential gene in it
351. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33606679
     Cyp33 binds AU-rich RNA motifs via an extended interface that competitively disrupts the gene repressive Cyp33-MLL1 interaction in vitro.

     Lloyd NR, Wuttke DS · PLoS ONE 2021
     used by PPIE (CyP33) — the off-switch the fusion throws away, and the reason PHD3 reinsertion kills transformation, What is lost: the PHD3/CYP33 switch that lets wild-type KMT2A turn itself off
352. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33581643
     Targeting critical kinases and anti-apoptotic molecules overcomes steroid resistance in MLL-rearranged leukaemia.

     de Groot AP, Saito Y, Kawakami E, Hashimoto M, Aoki Y, Ono R, et al. · EBioMedicine 2021
     used by Prednisolone - the active steroid, the drug every resistance experiment in this disease actually used, and the one given into the spinal fluid, The apoptotic priming state — KMT2A-rearranged infant ALL is the one childhood ALL subgroup that is BCL-2-dependent rather than BCL-XL-co-dependent, and BH3 profiling is how that was measured
353. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33805149
     Landscape of Chimeric RNAs in Non-Cancerous Cells

     Chen C, Haddox S, Tang Y, Qin F, Li H · Genes (Basel) 2021
     used by Read-through (cis-SAGe) chimeras: most 'fusions' called from RNA-seq in childhood ALL are normal conjoined genes
354. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset
     GSE139196: ChIP-seq on KAP1 in MCF-7 with and without estradiol, GSM5660804 and GSM5660805, hg38 HOMER peak files

     Yang F, Tanasa B, Micheletti R, Ohgi KA, Aggarwal AK, Rosenfeld MG · NCBI GEO 2021
     used by RUN: KAP1/TRIM28 has a called peak overlapping the KMT2A promoter in MCF-7 in both hormone conditions, 267 bp of it inside the K562 TRIM28 peak Q110 found - and its nearest chr11 peak to the exon-11 CTCF summit is 52,230 bp away, THE POSITIVE RESULT: the writer G9a, the reader HP1a and the scaffold KAP1 all sit on the KMT2A PROMOTER in MCF-7 at the 87.6th-98.9th percentile of 2,000 ACTIVE promoters - surviving the control that says an active promoter is ChIP-hot for everything - while none of the three is above the 75th percentile at the exon-11 anchor 52 kb away
355. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33555272
     RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia

     Matthijssens F, Sharma ND, Nysus M, Nickl CK, Kang H, Perez DR, et al. · J Clin Invest 2021
     used by RUNX2 - a direct KMT2A-chimera target and dependency in T-ALL, a patient-specific enhancer target in KMT2A::AFF1 B-ALL, and the gene a menin inhibitor represses to restore steroid sensitivity in t(4;11) infants
356. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34453201
     Evolutionary and functional relationships in the ribosome biogenesis SBDS and EFL1 protein families.

     Méndez-Godoy A, et al. · Mol Genet Genomics 2021
     used by SBDS - a ribosome-maturation factor whose loss causes a leukaemia-predisposition syndrome, and whose BioID neighbourhood contains AFF1, KMT2A, CDK9, PAF1 and LEDGF
357. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34440129
     BTK, NUTM2A, and PRPF19 Are Novel KMT2A Partner Genes in Childhood Acute Leukemia.

     Zerkalenkova E, Lebedeva S, Borkovskaia A, et al. · Biomedicines 2021
     used by Sequencing-based MRD: better than flow in paediatric B-ALL, and applied to infant KMT2A-rearranged disease exactly once, What this beat searched, what it rejected, and the two papers it could not read - after a fifth route rescued the third
358. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34330324
     TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation.

     Wang C, Songyang Z, Huang Y · Cell & Bioscience 2021
     used by SETDB1 (Q15047, KMT1E/ESET) - the second H3K9me3 writer: it represses the fusion's own targets via the PAF1 complex, it is required in fetal liver HSPCs and in leukaemic stem cells, and it is a broad dependency in half the CRISPR panel - three published directions that do not agree
359. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32306475
     SFPQ-ABL1-positive B-cell precursor acute lymphoblastic leukemias.

     Biloglav A, et al. · Genes, Chromosomes & Cancer 2021
     used by SFPQ / PSF (P23246) - the last of 21 fusion-construct partners without an entry, and it is itself the 5' half of an ALL fusion that puts ABL1 in the nucleus
360. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34003336
     Inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1/INI1 protein in a molecular subset of atypical teratoid/rhabdoid tumors.

     Pathak R, Zin F, Thomas C, Bens S et al. · Acta Neuropathol 2021
     used by SMARCB1 (BAF47/INI1/SNF5) - zero entries, zero mentions and, on the evidence, correctly so: it is lost in primary AML rather than required
361. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34154424
     Discovery of the SMYD3 Inhibitor BAY-6035 Using Thermal Shift Assay (TSA)-Based High-Throughput Screening.

     Gradl S, Steuber H, et al. · SLAS Discov 2021
     used by SMYD3 - a lysine methyltransferase with three claimed histone marks and one robust non-histone substrate, sitting on an HOXA9 feed-forward loop in MLL-AF9 AML and a fatty-acid-oxidation axis in CML stem cells, with zero interventional trials
362. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34215745
     SS18 regulates pluripotent-somatic transition through phase separation.

     Kuang J, Zhai Z, Li P, Shi R, Guo W, Yao Y, et al. · Nat Commun 2021
     used by SS18 - a SWI/SNF subunit that is itself a fusion partner in another cancer, and a lineage-independent dependency in KMT2A-rearranged lines
363. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33333262
     CRISPRi-mediated depletion of Spt4 and Spt5 reveals a role for DSIF in the control of HIV latency

     Krasnopolsky S, Novikov A, Kuzmina A, Taube R · Biochimica et Biophysica Acta - Gene Regulatory Mechanisms 1864(1):194656 2021
     used by SUPT4H1 (SPT4) — zero papers linking it to KMT2A, and the 138th most KMT2A-selective gene out of 17,728, SUPT5H (SPT5) — the pausing factor the KMT2A field has never studied, and the counted absence that undercuts 'the fusion hijacks pause release'
364. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     RCSB PDB entries 7KSO ('Cryo-EM structure of PRC2:EZH1-AEBP2-JARID2') and 7KSR ('PRC2:EZH1_A from a dimeric PRC2 bound to a nucleosome'), entry titles fetched from the RCSB entry API

     · RCSB Protein Data Bank 2021
     used by SUZ12 - the scaffold that holds PRC2 together and decides which PRC2 it is, required in this disease and studied in it exactly once
365. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
     PDB 6VIN: Crystallographic structure of the circularly permuted human Taspase1 protein

     Nagaratnam N, Delker SL, Jernigan R, et al. · RCSB Protein Data Bank 2021
     used by Taspase1 and its two KMT2A cleavage sites: an enzyme-substrate interface with four apo structures, one co-crystal with a small molecule, and no structure with MLL at all
366. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34934933
     Closantel is an allosteric inhibitor of human Taspase1.

     Luciano V, Proschak E, Langer JD, et al. · iScience 2021
     used by Taspase1 is what turns the reciprocal product into an oncoprotein - and it is a conditional oncogene because of it
367. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33705482
     Tet1 is not required for myeloid leukemogenesis by MLL-ENL in novel mouse models.

     Ono R, Masuya M, et al. · PLoS One 2021
     used by TET1 (LCX / CXXC6) - a CXXC reader that is also a KMT2A fusion partner, and whose leukaemic fusion throws its own CXXC domain away
368. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 32414848
     Combinatorial efficacy of entospletinib and chemotherapy in patient-derived xenograft models of infant acute lymphoblastic leukemia

     Loftus JP, Yahiaoui A, Brown PA, et al. · Haematologica 2021
     used by The 'infant ALL' PDX panel with four KMT2A::AFF1 models — one of which the full text calls adult
369. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     Expression changes after Inhibition of AHD in Molm-13 cells (GSE151660)

     GEO submitters · NCBI Gene Expression Omnibus 2021
     used by The AHD inhibitor's deposited arm is MOLM-13 and its in vivo arm is nowhere: a half-resolution that names the limit exactly
370. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33814344
     1,6-Hexanediol, commonly used to dissolve liquid-liquid phase separated condensates, directly impairs kinase and phosphatase activities

     Duster R, Kaltheuner IH, Schmitz M, Geyer M · Journal of Biological Chemistry 2021
     used by The case that the KMT2A-fusion condensate is an artefact — what 1,6-hexanediol, overexpressed tags and in-vitro droplets actually prove
371. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34698839
     Annual Report to the Nation on the Status of Cancer, Part 2: Patient Economic Burden Associated With Cancer Care

     Yabroff KR, Mariotto A, Tangka F, et al. · Journal of the National Cancer Institute 2021
     used by The cost of surviving: late effects carry a lifetime bill nobody has costed for infants
372. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34079898
     Chemical Inhibition of ENL/AF9 YEATS Domains in Acute Leukemia.

     Garnar-Wortzel L, Bishop TR, Kitamura S, Milosevich N, Asiaban JN, Zhang X, Zheng Q, Chen E, Ramos AR, Ackerman CJ, Hampton EN, Chatterjee AK, Young TS, Hull MV, Sharpless KB, Cravatt BF, Wolan DW, Erb MA · ACS Central Science 2021
     used by The days-long experiment that would close or confirm the imprinting liability: allele-specific XIST and MEG3 readout in cells treated with a YEATS antagonist, Which step is rate-limiting, and what compensates when you block it — the bite-back map for the causal chain
373. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33993518
     Structural characteristics of coiled-coil regions in AF10-DOT1L and AF10-inhibitory peptide complex.

     Zhou Z, Kang S, Huang Z, et al. · J Leukoc Biol 2021
     used by The DOT1L-AF10 octamer - the second route to H3K79 methylation, required in MLL-AF10 and absent from KMT2A::AFF1
374. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 34258738
     LEDGINs, Inhibitors of the Interaction Between HIV-1 Integrase and LEDGF/p75, Are Potent Antivirals with a Potential to Cure HIV Infection.

     Debyser Z, Bruggemans A, et al. · Adv Exp Med Biol 2021
     used by The HIV field is NOT drugging LEDGF: LEDGINs and ALLINIs bind integrase, and the proof is that they still work in a LEDGF knockout cell
375. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     GSE139199 (SuperSeries) series record: !Series_pubmed_id = 34194047; !Series_relation = SuperSeries of: GSE139137, GSE139138, GSE139196, GSE163494

     Yang F, et al. · NCBI GEO 2021
     used by Three archives, one answer: SUV39H1 has no ENCODE target record under any label (three routes, all empty), ChIP-Atlas's entire hg38 SUV39H1 holding IS the four GSE139196 MCF-7 samples re-indexed, and KMT2A is not among the 26 genes ChIP-Atlas calls SUV39H1 targets
376. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33961779
     Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy.

     Voisin N, Schnur RE, Douzgou S, Hiatt SM, Rustad CF, Brown NJ, Earl DL, Keren B, Levchenko O, Geuer S, Verheyen S, Johnson D, Zarate YA, Hančárová M, Amor DJ, Bebin EM, Blatterer J, Brusco A, Cappuccio G, Charrow J, Chatron N, Cooper GM, Courtin T, Dadali E, Delafontaine J, Del Giudice E, et al. · American Journal of Human Genetics 2021
     used by Three of the four AFF scaffolds have a named human Mendelian syndrome and the index fusion's partner has none — a 0/4 that is a fact about AFF1 and not about how hard anyone has looked, What the paralogues' disease biology says about AFF1: the AFF family shares one SIAH degron — and the index fusion DISCARDS it, because the whole degron lies in the AFF1 leader that the junction at residue 347 throws away
377. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34562451
     Posttranslational modifications of serine protease TMPRSS13 regulate zymogen activation, proteolytic activity, and cell surface localization.

     Martin CE, Murray AS, Sala-Hamrick KE et al · Journal of Biological Chemistry 2021
     used by TMPRSS13 (MSPL) - a cell-surface serine protease fused in frame to KMT2A exon 20, the clearest NOT-APPLICABLE epigenetics call of the seven, and a symbol whose approved form has a third of its alias's recall
378. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34728715
     Nucleolar translocation of human DNA topoisomerase II by ATP depletion and its disruption by the RNA polymerase I inhibitor BMH-21.

     Morotomi-Yano K, Yano KI · Sci Rep 2021;11:21533 2021
     used by TOP2A - the proliferation isoform, the one the drugs are actually measured against, and the only one with a germline association in this disease, TOP2B - the isoform most etoposide-induced KMT2A breaks depend on, resolved genetically and not resolvable pharmacologically
379. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33332189
     Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study.

     Peters C, Dalle JH, Locatelli F, Poetschger U, Sedlacek P, Buechner J, Shaw PJ, Staciuk R, et al. · Journal of Clinical Oncology 2021
     used by Total body irradiation and the age-four boundary - the best conditioning in childhood ALL has never been tested in the children who most need a transplant
380. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34830054
     The Fusion of CLEC12A and MIR223HG Arises from a trans-Splicing Event in Normal and Transformed Human Cells

     Dhungel BP, Monteuuis G, Giardina C, Bailey CG, Schmitz U, Rasko JEJ, et al. · International Journal of Molecular Sciences 2021
     used by Trans-splicing: healthy human cells make cancer-associated fusion transcripts without any chromosome rearrangement
381. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34323164
     A 2:1 randomized, open-label, phase II study of selinexor vs. physician's choice in older patients with relapsed or refractory acute myeloid leukemia

     Sweet K, Bhatnagar B, Döhner H, et al. · Leukemia & Lymphoma 2021
     used by Two reasons XPO1 is a hard target: every cell needs it, and blocking it switches on a survival pathway
382. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33390793
     Inhibition of USP1 induces apoptosis via ID1/AKT pathway in B-cell acute lymphoblastic leukemia cells

     · International Journal of Medical Sciences 2021
     used by USP1: an inhibitor, activity in B-ALL, and zero papers in the disease we care about
383. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 39506256
     Analytical Quality Controls for ddPCR Detection of Minimal Residual Disease in Acute Lymphoblastic Leukemia.

     Chen D, Sutton R, Giles J, et al. · Clin Chem 2021
     used by What MRD-negative actually means: a quantitative range, a laboratory judgement, and three incompatible definitions
384. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33451349
     Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia.

     Walker JS, Hing ZA, Harrington B, et al. · Journal of Hematology & Oncology 2021
     used by XPO1 / exportin-1 (CRM1) - the cell's main nuclear export receptor, and a chromatin-bound transcriptional scaffold, XPO1 E571K: a change-of-function hot spot in the NES-binding groove - and it does NOT confer resistance to the drugs that bind the same groove
385. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34048709
     N(6)-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation

     Cheng Y, et al. · Cancer Cell 2021
     used by YTHDC1 — the nuclear m6A reader in the MLL-METTL3-CTCF axis, with an inhibitor, and no dependency signal in KMT2A-rearranged lines
386. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34550965
     Interplay between the EMT transcription factors ZEB1 and ZEB2 regulates hematopoietic stem and progenitor cell differentiation and hematopoietic lineage fidelity

     Wang J, Farkas C, Benyoucef A, Carmichael C, Haigh K, Wong N, Huylebroeck D, Stemmler MP, Brabletz S, Brabletz T, Nefzger CM, Goossens S, Berx G, Polo JM, Haigh JJ · PLoS Biology 19:e3001394 2021
     used by ZEB2 — an EMT transcription factor that turns out to be a leukemia dependency and a guardian of lineage fidelity, ZEB2 level sets how easily a KMT2A-rearranged blast can change lineage under CD19-directed pressure
387. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 32461620
     Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1-KMT2A-YAP1 and VIM-KMT2A fusions.

     Massoth LR, Hung YP, Nardi V, et al. · Mod Pathol 2020
     used by 0.2% of profiled sarcomas, median age 38, and every number here has a denominator that is not the population, AHDC1 (Gibbin) - an AT-hook chromatin-architecture factor that is already a cofactor of a DIFFERENT sarcoma fusion oncoprotein, and whose KMT2A breakpoint lands in an untranslated exon, ARID1A (BAF250A) - required in the MLL-AF9 screen, present at the Myc enhancers, and flat in every selectivity measure, C2CD3 - the centriole-elongation regulator fused to KMT2A exon 8 in an MPNST, predicted OUT OF FRAME, and the partner whose RefSeq transcript is 390 residues shorter than UniProt's canonical, CPT1A - the outer-mitochondrial-membrane fatty-acid gatekeeper that is also a lysine succinyltransferase, fused to KMT2A exon 3 in the one case that is tether WITHOUT address, DOCK10 (Zizimin-3) - the Cdc42/Rac1 exchange factor fused to KMT2A exon 8 in an undifferentiated pleomorphic sarcoma, and the only one of the seven this graph already held as an H3K79me2-marked gene, ELP4 (PAXNEB) - a required subunit of Elongator, the one partner of the seven with a genuine histone-acetyltransferase connection, and the one whose fusion supplies only its last 43 residues, Every published KMT2A partner in sarcoma, counted - plus the papers this beat read and did not use, so the next beat does not repeat the search without the decisions, In leukaemia KMT2A gives the front of the protein; in sarcoma it gives the back. Every consequence follows from that., KMT2A-rearranged soft tissue sarcoma - the same gene as infant B-ALL, in a young adult's leg, as a solid tumour, RALGAPA2 (AS250) - the catalytic brake on RalA that behaves as a tumour suppressor, fused to KMT2A exon 22 in an osteosarcoma and predicted out of frame, which makes allele DISRUPTION the better hypothesis than a chimera, Seven KMT2A-rearranged sarcomas retain the menin-binding motif, three of them carry the complete leukaemic N-terminal module, and all sixteen partner names were in one unopened supplementary table, TMPRSS13 (MSPL) - a cell-surface serine protease fused in frame to KMT2A exon 20, the clearest NOT-APPLICABLE epigenetics call of the seven, and a symbol whose approved form has a third of its alias's recall, Two hypotheses in this graph make the same prediction on every lesion that exists, and the experiment queued to test them picks the one arm where neither speaks, VIM / vimentin (P08670) - a pan-MLL-fusion prey with a clean negative control, and separately a genuine KMT2A rearrangement partner in sarcoma, which are two different facts, VIM::KMT2A - the one KMT2A rearrangement that keeps the SET domain and still throws away the menin-binding exon, Which KMT2A exon carries which interface: exon 1 is the menin-binding motif, exons 5-6 are the CXXC zinc finger (computed, not recalled), YAP1 (P46937) - the Hippo pathway's transcriptional co-activator, and a KMT2A fusion partner from a completely different functional class, YAP1::KMT2A::YAP1 (YKY) - an insertional KMT2A rearrangement that keeps the CXXC zinc finger and throws the menin-binding exon away
388. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31592798
     Recurrent YAP1 and KMT2A Gene Rearrangements in a Subset of MUC4-negative Sclerosing Epithelioid Fibrosarcoma.

     Kao YC, Lee JC, Zhang L, et al. · Am J Surg Pathol 2020
     used by 0.2% of profiled sarcomas, median age 38, and every number here has a denominator that is not the population, In leukaemia KMT2A gives the front of the protein; in sarcoma it gives the back. Every consequence follows from that., KMT2A-rearranged soft tissue sarcoma - the same gene as infant B-ALL, in a young adult's leg, as a solid tumour, The menin interface is a requirement of 5'-KMT2A fusions in haematopoiesis, not of KMT2A rearrangement as such - and a solid tumour has been quietly proving it for six years, Two hypotheses in this graph make the same prediction on every lesion that exists, and the experiment queued to test them picks the one arm where neither speaks, VIM::KMT2A - the one KMT2A rearrangement that keeps the SET domain and still throws away the menin-binding exon, YAP1::KMT2A::YAP1 (YKY) - an insertional KMT2A rearrangement that keeps the CXXC zinc finger and throws the menin-binding exon away
389. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31913156
     Recurrent Fusions Between YAP1 and KMT2A in Morphologically Distinct Neoplasms Within the Spectrum of Low-grade Fibromyxoid Sarcoma and Sclerosing Epithelioid Fibrosarcoma.

     Puls F, Agaimy A, Flucke U, et al. · Am J Surg Pathol 2020
     used by 0.2% of profiled sarcomas, median age 38, and every number here has a denominator that is not the population, Every published KMT2A partner in sarcoma, counted - plus the papers this beat read and did not use, so the next beat does not repeat the search without the decisions
390. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31343482
     Inv(11)(q21q23); KMT2A-MAML2, a Recurrent Genetic Abnormality in T-Cell Therapy-related Acute Lymphoblastic Leukemia.

     Mariani RA, Silva M, Caparelli E, Jennings LJ, Yap KL, Leuer KM, Weinstein J, Gong S · Journal of Pediatric Hematology/Oncology 2020
     used by A child who made a KMT2A fusion during chemotherapy, lost it again, and never got leukaemia in 12.8 years, A KMT2A fusion is necessary but not sufficient: the cell it lands in decides whether there is a disease and which one, KMT2A::MAML2 keeps MAML2's activation domain and loses its Notch-binding domain, and suppresses Notch output, KMT2A::MAML2, inv(11)(q21q23) - a therapy-related fusion that also causes a solid tumour
391. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32923872
     Pan-Cancer Landscape Analysis Reveals Recurrent KMT2A-MAML2 Gene Fusion in Aggressive Histologic Subtypes of Thymoma.

     Massoth LR, Hung YP, Dias-Santagata D, Onozato M, Shah N, Severson E, Duncan D, Gillespie BJ, Williams NF, Ross JS, Vergilio JA, Harkins SK, Glomski K, Nardi V, Zukerberg LR, Hasserjian RP, Louissaint A, Williams EA · JCO Precision Oncology 2020
     used by A KMT2A fusion is necessary but not sufficient: the cell it lands in decides whether there is a disease and which one, Is KMT2A::AFF1 leukemia epithelial or endothelial? No — it is haematopoietic. But the question is a good one, Is the menin interface a property of the fusion or of the blood? Test KMT2A::MAML2 thymoma, KMT2A::MAML2 type B2/B3 thymoma - the same fusion, a different organ, a different disease, KMT2A::MAML2, inv(11)(q21q23) - a therapy-related fusion that also causes a solid tumour, MAML2 (mastermind-like 2) - the Notch co-activator that is a KMT2A partner in leukaemia and in thymoma, MAML2 exon 2: the strongly preferred 3' acceptor, the same in leukaemia, thymoma and salivary-gland tumours
392. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32552847
     The lncRNA LAMP5-AS1 drives leukemia cell stemness by directly modulating DOT1L methyltransferase activity in MLL leukemia.

     Wang WT, Chen TQ, Zeng ZC, et al. · J Hematol Oncol 2020
     used by A long non-coding RNA binds DOT1L's catalytic domain and turns its activity up - and blocking it makes the fusion protein itself get eaten
393. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32456310
     MAT2A as Key Regulator and Therapeutic Target in MLLr Leukemogenesis

     · Cancers 2020
     used by A methionine rescue arm, which separates SAM limitation from ordinary cytotoxicity, If inhibiting one methyltransferase failed, constraining the methyl donor may not, MAT2A - the enzyme that makes the methyl donor, and the one metabolic dependency in this disease with two independent papers and a lymphoid PDX result, SAM supply sustains the KMT2A-rearranged hypermethylated state - the metabolic requirement that IS a consequence of the chromatin programme, and can be attacked as one, The experiment that separates lineage from ontogeny: one KMT2A fusion, two cell-of-origin contexts, three metabolic perturbations, and a limiting-dilution readout alongside the viability one
394. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 32937789
     Comprehensive Analysis of MEN1 Mutations and Their Role in Cancer.

     Nelakurti DD, Pappula AL, Rajasekaran S, Miles WO, Petreaca RC · Cancers 2020
     used by A residue axis for menin, derived from coordinates: three spatial lobes, not four named ones, and the sharpest seam in the protein runs through the drug pocket
395. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32294539
     The reciprocal world of MLL fusions: A personal view.

     Marschalek R · Biochim Biophys Acta Gene Regul Mech 2020
     used by About one KMT2A-rearranged patient in twenty has no direct fusion at all - only the reciprocal one, At the DNA level almost every KMT2A-rearranged patient has a reciprocal allele - 94% across partners, and 5% have nothing else, Competing model 2: the reciprocal allele is lost as the leukaemia evolves, and losing it selects for something worse, Enumeration of the reciprocal KMT2A fusion literature: what was searched, found, rejected and could not be read, In the only panel that tested both halves of four translocations, 3 of 4 reciprocal fusions transformed and only 1 of 4 direct ones did, Reciprocal status is a different fact depending on whether you assay DNA or RNA, and the whole prognostic literature is RNA, t(6;11) makes four fusion genes, not two, and the PHD/bromodomain cassette is what opens chromatin in all of them
396. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31558671
     Transforming activities of the NUP98-KMT2A fusion gene associated with myelodysplasia and acute myeloid leukemia.

     Fisher JN, Thanasopoulou A, Juge S, et al. · Haematologica 2020
     used by About one KMT2A-rearranged patient in twenty has no direct fusion at all - only the reciprocal one, An H3K4me3-reading PHD finger fused to NUP98 makes a potent leukaemia oncoprotein; the H3K4me3-reading PHD finger of KMT2A is deleted from every KMT2A fusion and reinstating it abolishes transformation. Same module class, opposite sign - and the one NUP98 fusion that carries KMT2A's PHD cassette is the weakest member of its family., Bounded absence: not one menin-inhibitor study, trial or preclinical paper has ever recorded reciprocal fusion status, In the only cohort that measured it, HOXA genes are ON in exactly the reciprocal-positive patients and OFF in the rest, Menin dependency tracks the availability of an intact menin-binding motif, in cis or in trans — not the fusion family, Menin primacy was established on the der(11) product alone and has never been tested against the der(4) product, NUP98::KMT2A, inv(11)(p15q23) — the NUP98 fusion that contains KMT2A and is menin-inhibitor RESISTANT, NUP98::NSD1, t(5;11)(q35;p15.5), Stratify an existing menin-inhibitor cohort by reciprocal fusion status, The graph's universal 'every KMT2A fusion loses the SET domain' is a silent, propagating error class, Two classes of KMT2A rearrangement keep the SET domain, and the graph says otherwise, Two constructs that would decide whether menin dependency is about the menin-binding motif or about HOXA level, Two hypotheses in this graph make the same prediction on every lesion that exists, and the experiment queued to test them picks the one arm where neither speaks, Why a nucleoporin fusion needs menin-MLL1: the second menin-dependent fusion family, and what it borrows rather than carries
397. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32646642
     Combined inhibition of menin-MLL interaction and TGF-beta signaling induces replication of human pancreatic beta cells.

     Pahlavanneshan S, Behmanesh M, Oropeza D, Furuyama K, Tahamtani Y, Basiri M, Herrera PL, Baharvand H · Eur J Cell Biol 2020
     used by Absence: the tissue with the clinical signal is the one tissue nobody has put under a menin inhibitor and measured - one record in the whole literature, and it is a review, Hypothesis: the menin-MLL complex writes the same mark onto two address lists with opposite cell-state outputs, and which one a tissue reads decides whether blocking menin is a therapy or a lesion, MEN1 / menin — the adaptor the fusion cannot work without, Menin inhibition makes adult human beta cells divide in a dish - the hardest thing in beta-cell biology, Menin's other address list: the same complex that switches on HOXA in blood writes H3K4 methylation onto the CDK inhibitors p27 and p18 in endocrine cells, The endocrine cell's resting state is an actively maintained G1 restraint, and menin is what maintains it, The same drug target, pursued for benefit: menin inhibition is a diabetes strategy in the literature
398. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31515871
     Cryptic recurrent ACIN1-NUTM1 fusions in non-KMT2A-rearranged infant acute lymphoblastic leukemia

     Pincez T, Landry JR, Roussy M, et al. · Genes, Chromosomes and Cancer 2020
     used by ACIN1 (Acinus) - a splicing/apoptosis protein whose only domain is the 35-residue module the leukaemic fusion keeps, and whose entire localization record is uncoded, ACIN1::NUTM1 - the commonest NUTM1 fusion in infants, cryptic to cytogenetics, and the only one with a human cell line, NUTM1-rearranged B-ALL - the KMT2A-wild-type arm of the same infant trials, with 4-year EFS of 100% against 36-37% next door
399. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32268092
     Super Elongation Complex as a Targetable Dependency in Diffuse Midline Glioma.

     Dahl NA, Danis E, et al. · Cell reports 2020
     used by AFF4 has never been placed in a haematopoietic cell state — every SEC cell-state result is in another tissue
400. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32719551
     Biophysical properties of AKAP95 protein condensates regulate splicing and tumorigenesis.

     Li W, Li W, Hu J, Shi B, Palomba F, Digman MA, Gratton E, Jiang H · Nat Cell Biol 2020
     used by AKAP8 (AKAP95) - the only nuclear A-kinase anchoring protein, and the one that turned out to be required for MLL-rearranged leukaemia
401. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32402250
     RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia

     Shen C, et al. · Cell Stem Cell 2020
     used by ALKBH5 — the second m6A eraser: a cancer-stem-cell self-renewal role elsewhere, one incidental KMT2A record, and a flat dependency row
402. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32021283
     ASH2L-Promoted HOXC8 Gene Expression Plays a Role in Mixed Lineage Leukemia-Rearranged Acute Leukemia.

     Wu YJ, Li LX, Liu L, et al. · Onco Targets Ther 2020
     used by An anti-MLL-C antibody in a t(4;11) cell is looking at two proteins at once, ASH2L is studied in leukaemia and has never been placed in a cell state there — and the KMT2A-rearranged arm needs it LESS than average, ASH2L: the only WRAD subunit ever perturbed in a KMT2A::AFF1 cell, once, weakly, RBBP5: the thinnest fusion literature of the four subunits, and one chromatin datum, The bite-back of striking a target: a wrong strike costs a cure and generates no data that it was wrong
403. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32207970
     A Binary Arginine Methylation Switch on Histone H3 Arginine 2 Regulates Its Interaction with WDR5.

     Lorton BM, Harijan RK, Burgos ES, Bonanno JB, et al. · Biochemistry 2020
     used by An assay that cannot separate me2a from me2s cannot test the arginine switch - the two states are isobaric and predict OPPOSITE things, so a non-discriminating readout returns no information rather than an imprecise answer, Arginine methylation gates KMT2-complex access to chromatin at two residues, in both directions, independently of the menin tether AND of the WIN motif - a parallel control point, not a rival to menin dependence, H3R2me2a - the asymmetric arginine mark two residues from H3K4 that LOCKS the WRAD module off the histone tail, and the first arginine mark node in this graph, H3R2me2s - the symmetric mark on the SAME residue as H3R2me2a, which permits rather than enhances WRAD access, and whose 'enhancing' half this graph inherited from the paper that was later revised
404. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32188505
     Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL

     Wierzbinska JA, Toth R, Ishaque N, et al. · Genome Medicine 2020
     used by Analysis (runnable): build a methylome cell-of-origin score for infant KMT2A-rearranged ALL and test it as a predictor of lineage destination, Hypothesis: where a blast goes when the fusion program is released is written in its methylome at diagnosis, not in its transcriptome, Pentimento and restoration — the fusion overpaints the cell, and cleaning reveals whatever was underneath
405. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32766858
     Exploitable metabolic dependencies in MLL-ENL-induced leukemia

     Garcia-Cuellar MP, ... Slany RK · Blood Advances 2020
     used by Analysis: cross-validating the single-group non-menin KMT2A-fusion dependencies in one framework, BCAT1 in core-binding-factor AML - the closest analogue in another fusion family, where TWO different fusions converge on one metabolic enzyme by rewiring the chromatin at its locus, Is the metabolic phenotype a consequence of the fusion programme or an independent dependency? The answer is that BOTH directions are published, and one of them points the other way entirely, Metabolic enzyme enumeration in KMT2A-rearranged leukaemia: the instrument, its positive controls, seventeen bounded absences - and the counted zero that would have been wrong, PTBP1 — the strongest RNA-layer dependency in KMT2A-rearranged lines, found by a domain-focused screen and missed by this beat's own gene panel, Serine/glycine dependence in MLL-ENL leukaemia, reached through a DIRECT fusion target gene - and the reason a PHGDH counted absence in this graph would have been wrong, The second ring — smaller KMT2A-fusion mechanism labs, and where the literature actually points
406. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33144337
     Myeloid transformation by MLL-ENL depends strictly on C/EBP

     Wesolowski R, ... Leutz A · Life Science Alliance 2020
     used by Analysis: cross-validating the single-group non-menin KMT2A-fusion dependencies in one framework, The second ring — smaller KMT2A-fusion mechanism labs, and where the literature actually points
407. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32152128
     DBC1, p300, HDAC3, and Siah1 coordinately regulate ELL stability and function for expression of its target genes.

     Basu S, Barad M, Yadav D, et al. · Proc Natl Acad Sci U S A 2020
     used by Anti-ELL antibodies carry a confound the other partners do not: two paralogues and a protein whose abundance is actively regulated
408. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31756535
     Anti-Thymocyte Globulin Prophylaxis Induces a Decrease in Naive Th Cells to Inhibit the Onset of Chronic Graft-versus-Host Disease: Results from the Canadian Bone Marrow Transplant Group (CBMTG) 0801 Study.

     Naeije L, Kariminia A, Abdossamadi S, Azadpour S, Subrt P, Kuzeljevic B, Irvine M, Chan G, et al. · Biology of Blood and Marrow Transplantation 2020
     used by Anti-thymocyte globulin - a rabbit antibody against human T cells, given to infants at a fixed mg/kg dose against a T-cell mass that nobody measures
409. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 34386776
     Dual ARID1A/ARID1B loss leads to rapid carcinogenesis and disruptive redistribution of BAF complexes

     Wang Z, Chen K, Jia Y, Chuang JC, Sun X, Lin YH, et al. · Nat Cancer 2020
     used by ARID1B (BAF250b) - the cBAF paralogue whose deletion PROMOTES MLL-AF9 leukaemogenesis, which makes it the one gene in this beat whose published KMT2A-fusion result points the wrong way for a drug target
410. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32270036
     ENL initiates multivalent phase separation of the super elongation complex (SEC) in controlling rapid transcriptional activation.

     Guo C, Che Z, Yue J, et al. · Science advances 2020
     used by Attribution audit 3 of 5 - where KMT2A::AFF1 sits in the nucleus: the endogenous image does not survive, the overexpression images do and say something different, Counted absence: AFF1/AF4 - the partner in the commonest infant fusion - has no phase-separation literature under any alias, and the two hits that look like it are token collisions, ENL's disordered region and condensates, restricted to what actually bears on KMT2A::MLLT1 - which is one figure panel, ENL's nuclear annotation has no citation at all, and every picture of ENL in a nucleus is of a mutant or a fusion, never the wild-type protein, How P-TEFb gets out of the reservoir: a dephosphorylation, a dissociation, and a reassembly on whichever scaffold is waiting, KMT2A::MLLT1 engages P-TEFb through one 66-residue surface: the ENL AHD, residues 494-559, and L550E breaks it, The case that the KMT2A-fusion condensate is an artefact — what 1,6-hexanediol, overexpressed tags and in-vitro droplets actually prove, The KMT2A::MLLT1 mechanism sweep: what was searched, what was read and not used, and the three retrieval traps that would have produced confident wrong answers, The only cellular proposal for how the SEC gets P-TEFb out of the reservoir is a condensate, and the two assays it rests on cannot tell that model from its rival, The strongest published case that condensates are load-bearing in KMT2A-fusion leukemia — and it is AKAP95, not AFF1, Transcription factories and Pol II clusters - no KMT2A::AFF1 imaging, condensate evidence for SEC and MLL-ENL, and 3D-FISH that actively contradicts the factory story for t(4;11), Where KMT2A and its fusions sit inside the nucleus — SNL1/SNL2, nuclear speckles and the condensate question, Where KMT2A::MLLT1 actually sits: chromatin occupancy is mapped, subnuclear localisation of the endogenous fusion has never been imaged
411. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33139953
     BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis

     Fan H, Lu J, Guo Y, Li D, Zhang ZM, Tsai YH, et al. · Nat Genet 2020
     used by BAHCC1 - a BAH-domain H3K27me3 reader that an MLL fusion binds and upregulates in mouse, and the locus carrying the two largest MLL1-N-reactive rises under a menin inhibitor in human RS4;11
412. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31974170
     Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia.

     Pei S, Pollyea DA, Gustafson A, Stevens BM, Minhajuddin M, Fu R, et al., Jordan CT · Cancer Discovery 2020
     used by BCL2 — the one co-dependency in this beat that already has an approved drug pointed at it, GMP-like state — the destination of therapy-driven lineage switch and, separately, the state most sensitive to menin inhibition, Hypothesis: the haem and iron dependency of KMT2A-rearranged lines is monocytic physiology, not fusion biology — and the panel cannot tell us either way, Import class 5: evidence borrowed from fusions that are not KMT2A fusions at all, Monocyte — the graph's most-discussed undefined cell identity, and the confound sitting under its own DepMap haem signal, Settle the monocytic confound isogenically: degrade the fusion, read haem-gene dependency before lineage has time to move
413. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32954361
     BCOR binding to MLL-AF9 is essential for leukemia via altered EYA1, SIX, and MYC activity

     Schmidt CR, Achille NJ, Kuntimaddi A, et al. · Blood Cancer Discovery 2020
     used by BCOR — the other side of the CBX8 conflict, and a target you would be inhibiting in the direction of disease, BCOR, not CBX8, is the AHD contact MLL-AF9 cannot lose - and the same two partners bind ENL far more tightly than AF9, CBX8 — the one place in this interactome where two good papers flatly disagree, and DepMap takes a side, Does the fusion's programme fall apart in the same order in KMT2A::AFF1 as in MLL::AF9? The chain's only ordering measurement, repeated on the index fusion, DOT1L — the target where excellent chemistry met an indirect interaction, KDM2B — 513 potent ChEMBL rows that are mostly patent bins, and no structure of the domain they claim to inhibit, KOPB-26 (CVCL_7972): a t(9;11) B-ALL line from a 13-month-old, and the model for 42% of this partner's patients that nobody uses, Polycomb in KMT2A-r leukemia — core PRC2 required, EZH2 and BMI1 dispensable, and CBX8 acting outside its repressive role, The order in which the fusion's programme collapses is a property of the partner, not of KMT2A - so there is no single causal chain
414. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32628469
     Structure and Role of BCOR PUFD in Noncanonical PRC1 Assembly and Disease

     Wong SJ, Senkovich O, Artigas JA, Gearhart MD, Ilangovan U, Graham DW, Abel KN, Yu T, Hinck AP, Bardwell VJ, Kim CA · Biochemistry 59(29):2718-2728 2020
     used by BCORL1 — the BCOR paralogue that is in the only crystal structure of the PRC1.1 core, and is the one PRC1.1 subunit nobody has tested in KMT2A-rearranged leukaemia, PRC1.1 — the complex this graph has been leaning on, now enumerated subunit by subunit, and the enumeration changes the conclusion
415. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 32277283
     Characterization of therapy-related acute leukemia in hereditary breast-ovarian carcinoma patients: role of BRCA1 mutation and topoisomerase II-directed therapy.

     Bagal B, Kumar R, Gaur T, Talreja V, Bonda A, Patkar N, Shetty D, Kowtal P, Subramanian PG, Gupta S, Sarin R, Hasan SK · Medical Oncology 2020
     used by BRCA1 (P38398, 1,863 aa) - named in 19 entries of this graph and never written: the HR mediator that CTCF and the H3K9 machinery are now reported to license at a break, and the only cascade member with a human therapy-related-leukaemia signal after topoisomerase II therapy, Giving a G9a/GLP inhibitor alongside etoposide or doxorubicin removes a DNA-repair licence at the moment TOP2 breaks are being made - and the sibling compound UNC-0638 is measured to block BRCA1/BARD1 arrival at a break, in children on curative therapy
416. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32398829
     SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations.

     Takedachi A, Despras E, et al. · Nat Struct Mol Biol 2020
     used by BRIP1 — downstream effector; rank 22 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all, Transcription–replication conflict as the candidate reason KMT2A-rearranged cells need the Fanconi pathway — a chain with two measured links and three inferred ones
417. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32460032
     CXCR4 Signaling Has a CXCL12-Independent Essential Role in Murine MLL-AF9-Driven Acute Myeloid Leukemia

     Ramakrishnan R, Pena-Martinez P, Agarwal P, Rodriguez-Zabala M, Chapellier M, Hogberg C, et al. · Cell Reports 2020
     used by CAR cell (CXCL12-abundant reticular) / LEPR+ perivascular stromal cell — the cell that makes the signal holding blood stem cells in the marrow, CXCL12 (SDF-1) - the marrow retention chemokine this graph already had a mechanism entry for and no entry for the protein, CXCL12-CXCR4 retention — the axis everyone calls the niche dependency, and the CRISPR screen that says the ligand is not required, CXCR4 - named in eighteen entries of this graph with no entry of its own, and the one niche molecule with a drug, a paediatric trial and a direct KMT2A-r experiment, CXCR4 function in KMT2A-rearranged blasts is an output of the fusion's own HOXA/MEIS1 program, so a menin inhibitor should switch off the niche axis without a CXCR4 antagonist, Experiment: give an antioxidant with the CXCR4 antagonist — if the drug stops working, the niche is a redox buffer and not a hiding place
418. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32347296
     Identification of co-expressed genes associated with MLL rearrangement in pediatric acute lymphoblastic leukemia.

     Zhang H, Liu B, Cheng J, Ma H, Li Z, Xi Y · Biosci Rep 2020
     used by CD15 (Lewis-x, SSEA-1, 3-fucosyl-N-acetyllactosamine) - a sugar, not a protein: the most-named antigen in this graph that no gene encodes, FUT4 - the myeloid alpha-1,3-fucosyltransferase, a hub gene of the KMT2A-rearranged expression module, and the gene HGNC once officially called CD15
419. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33220589
     Expression of putative leukemia stem cell targets in genetically-defined acute myeloid leukemia subtypes.

     Yanagisawa B, Perkins B, Karantanos T, Levis M, Ghiaur G, Smith BD, et al. · Leuk Res 2020
     used by CLEC12A (CD371, CLL-1, MICL) - the leukaemic-stem-cell antigen whose therapeutic rationale rests on an absence, and which menin inhibition appears to induce
420. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32517300
     Only Hematopoietic Stem and Progenitor Cells from Cord Blood Are Susceptible to Malignant Transformation by MLL-AF4 Translocations

     · Cancers 2020
     used by Cord blood does transform — when the translocation is engineered rather than expressed
421. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33033246
     In vivo CRISPR/Cas9 targeting of fusion oncogenes for selective elimination of cancer cells

     Martinez-Lage M, Torres-Ruiz R, Puig-Serra P, Moreno-Gaona P, Martin MC, Moya FJ, et al. · Nature Communications 2020
     used by Correcting the fusion with genome editing: verdict NOT FEASIBLE for infant leukaemia, though intron-targeted disruption is a real published strategy
422. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.journal-articlePMID 31325323
     Potent antileukemic activity of curaxin CBL0137 against MLL-rearranged leukemia

     · International Journal of Cancer 2020
     used by Counted absences keyed on a complex subunit miss the papers that name only the complex - demonstrated on our own SSRP1 entry, which declared no KMT2A paper about FACT while this graph cites one about the index fusion in four other entries, FACT (SPT16-SSRP1) - the chromatin arm of transcription elongation, and a clean negative result for the KMT2A::AFF1 interactome, Interactome round 5: 42 queries, 13 entries written, 9 candidates rejected with counts, and four alias failures of four different kinds, SSRP1 - the small FACT subunit, and the only protein in this beat that binds a confirmed KMT2A-fusion interactor directly (LEDGF/p75, via HMG box to PWWP), SUPT16H (SPT16) - the large FACT subunit: pan-essential, an anti-dependency in KMT2A-rearranged lines, and drugged in MLL-r leukaemia by a compound that works through p53
423. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32338903
     Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin-MLL Interaction with Strong In Vivo Antitumor Activity

     · Journal of Medicinal Chemistry 2020
     used by Covalent or reversible is the axis on which ‘the menin inhibitor class’ most plausibly breaks, M-808 — a covalent menin-MLL inhibitor with a co-crystal, five years before the graph noticed it
424. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32426500
     Competition between PAF1 and MLL1/COMPASS confers the opposing function of LEDGF/p75 in HIV latency and proviral reactivation.

     Gao R, Bao J, Yan H, et al. · Sci Adv 2020
     used by CSNK2A1 (casein kinase 2 alpha) - the one kinase that turns up three separate times in KMT2A biology
425. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     GSE149183 series supplementary files: RS4_11 H3K79me2 TSS-ChIPseq signal + dm6 spike-in sitepro table

     Perner F, Gadrey JY, Xiong Y, et al. · NCBI Gene Expression Omnibus 2020
     used by Cycle 110's 'D10 GAINED 66%' rescored on the absolute scale: D10 lost 76.5% of its H3K79me2, no stratum gained anything, and on the genuine RS4;11 rows the gradient spans 41-fold against the contaminated table's 30-fold, Day 3 of a DOT1L inhibitor has already removed 85-90% of H3K79me2 absolutely, and the collapse becomes progressively LESS uniform: the p10-p90 spread of per-gene retention widens from 2.4-fold at d3 to 8-44-fold at d9 in all four arms, Every per-sample normalisation is a constant multiplier: it never changes the shape, it only moves the line between 'gained' and 'lost' - which is why 'share', 'raw' and 'absolute' give the same ranking and three different answers to 'did this go up?', On an absolute scale, H3K79me2 in the index fusion falls 52-fold (EPZ5676) to 91-fold (compound 10) by day 9 and NOT ONE of 17,341 measurable genes holds its signal - the first absolute-scale chromatin statement this project has been able to make about KMT2A::AFF1, On the absolute scale the H3K79me2 gradient is real and it runs the other way from the share: the most heavily marked decile retains 0.8% and the least marked retains 31%, a 41-fold gradient - and every decile, in both lines and under both drugs, still loses, RS4;11 retains 2.5x more H3K79me2 than MOLM13 under EPZ5676 at every one of ten baseline deciles - and 0.71x under compound 10, with the sign reversing in deciles 5-10: the between-line difference survives the baseline confound and fails the drug replication, so it cannot be attributed to the fusion partner, Six to twenty-four libraries in RS4;11: two DOT1L inhibitors titrated to equal spike-in-measured global H3K79me2 loss, three replicates per arm, plus the no-primary control that no public deposit contains - the smallest experiment that would convert four moderate entries in this beat into testable ones, The deposited RS4;11 H3K79me2 table in GSE149183 is two-thirds MOLM13: 38,580 of its 57,794 rows are byte-for-byte identical to the MOLM13 file, so the index fusion is measurable at only 19,214 TSS entries, The GSE149183 per-gene columns are RAW, not spike-in scaled: every one of 1,040,292 values in both files sits exactly on a 0.04 grid, which no per-library scale factor survives - so two entries in this graph called an unscaled number absolute, and the true collapse is 37-91x, not 5.8x, The same baseline-matched test that kills the target effect under EPZ5676 fires hard under compound 10 - at d6 and d9, in both cell lines, 4 of 4 contrasts (p = 0.0012 to <0.0001) - and in MOLM13 HOXA9 holds 24.5% of its H3K79me2 where the genome median holds 4.5%, Two inhibitors of the same DOT1L active site leave different residual H3K79me2 landscapes, and the difference sits at the KMT2A-fusion target loci - so 'how much H3K79me2 is left' is a compound-specific readout, not a generic measure of DOT1L inhibition, Under EPZ5676 the canonical KMT2A-fusion targets look like they lose H3K79me2 far more than the genome (p=0.017 and p=0.0004), and against a baseline-matched null the entire effect vanishes (p=0.34 and p=0.22) - eight of the ten are simply top-decile genes
426. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 32575123
     Novel inhibitors of the histone methyltransferase DOT1L show potent antileukemic activity in patient-derived xenografts.

     Perner F, Gadrey JY, Xiong Y, Hatton C, Eschle BK, Weiss A, et al. · Blood 2020
     used by Cycle 110's 'D10 GAINED 66%' rescored on the absolute scale: D10 lost 76.5% of its H3K79me2, no stratum gained anything, and on the genuine RS4;11 rows the gradient spans 41-fold against the contaminated table's 30-fold, Day 3 of a DOT1L inhibitor has already removed 85-90% of H3K79me2 absolutely, and the collapse becomes progressively LESS uniform: the p10-p90 spread of per-gene retention widens from 2.4-fold at d3 to 8-44-fold at d9 in all four arms, First deposit to put both drug classes on the MEN1 channel in one experiment: VTP-50469 leaves ZERO of the 19 DMSO menin peaks at 15 canonical menin-MLL target loci, while EPZ5676 keeps 14, compound 10 keeps 14 and compound 11 keeps 8 - strength-matched permutation p = 0.0003, and the zero is unchanged at every flank from 0 to 100 kb, Novartis 'compound 10' - a DOT1L methyltransferase inhibitor from Perner et al. (Blood 2020), active at 100 nM, whose chemical structure is not given in the GEO deposit and whose target engagement at that dose IS demonstrated in the same series by a 5.6-fold spike-in-normalised H3K79me2 collapse by day 3, Novartis 'compound 11' - a DOT1L methyltransferase inhibitor from Perner et al. (Blood 2020), active at 100 nM, whose chemical structure is not given in the GEO deposit and whose target engagement is not measured anywhere in the series, On an absolute scale, H3K79me2 in the index fusion falls 52-fold (EPZ5676) to 91-fold (compound 10) by day 9 and NOT ONE of 17,341 measurable genes holds its signal - the first absolute-scale chromatin statement this project has been able to make about KMT2A::AFF1, The deposited RS4;11 H3K79me2 table in GSE149183 is two-thirds MOLM13: 38,580 of its 57,794 rows are byte-for-byte identical to the MOLM13 file, so the index fusion is measurable at only 19,214 TSS entries, The GSE149183 per-gene columns are RAW, not spike-in scaled: every one of 1,040,292 values in both files sits exactly on a 0.04 grid, which no per-library scale factor survives - so two entries in this graph called an unscaled number absolute, and the true collapse is 37-91x, not 5.8x, The same baseline-matched test that kills the target effect under EPZ5676 fires hard under compound 10 - at d6 and d9, in both cell lines, 4 of 4 contrasts (p = 0.0012 to <0.0001) - and in MOLM13 HOXA9 holds 24.5% of its H3K79me2 where the genome median holds 4.5%, Two inhibitors of the same DOT1L active site leave different residual H3K79me2 landscapes, and the difference sits at the KMT2A-fusion target loci - so 'how much H3K79me2 is left' is a compound-specific readout, not a generic measure of DOT1L inhibition
427. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 32845001
     A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial.

     Tomizawa D, Miyamura T, Imamura T, Watanabe T, Moriya Saito A, Ogawa A, et al. · Blood 2020
     used by Cytarabine - the one conventional drug KMT2A-rearranged infant ALL is MORE sensitive to, and the only case in this beat where a mechanism changed a protocol, Dying in induction: the place where infant protocols actually differ, JPLSG MLL-10 (n=90 infants): a 38-point EFS split built from age, CNS status and MRD, with the partner never entering the model, Pallor and anaemia in infants: the number this graph quotes does not exist for babies, Two cohorts, a hundred infants each, and opposite answers on which sex does worse, WBC 300, age 6 months, MRD 0.01%: three lines drawn by committees, not by biology
428. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33077595
     DOT1L-controlled cell-fate determination and transcription elongation are independent of H3K79 methylation.

     Cao K, Ugarenko M, Ozark PA, et al. · Proc Natl Acad Sci U S A 2020
     used by Degrade DOT1L, inhibit DOT1L, or leave a dead enzyme in place - run all three against the same cells and the same marrow, DOT1L does things that have nothing to do with methylation - which is why blocking its active site was never going to remove all of it, DOT1L was not refuted - the wrong thing was blocked, at a dose nobody finished escalating
429. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32934780
     Targeted CRM1-inhibition perturbs leukemogenic NUP214 fusion proteins and exerts anti-cancer effects in leukemia cell lines with NUP214 rearrangements.

     Mendes A, Jühlen R, Martinelli V, et al. · Oncotarget 2020
     used by DEK::NUP214 is the sixth lesion on the XPO1 address - and the only one where the drug response was measured in primary patient cells, NUP214 / CAN - the cytoplasmic-face nucleoporin that CRM1 docks against, and the 3' partner of four leukaemia fusions, SET::NUP214 has no address of its own: chromatin-bound CRM1 is already at HOX, and the fusion's FG repeats dock onto it, Where SET::NUP214 actually is: mobile intranuclear bodies that trap CRM1, dissolve in mitosis and under CRM1 inhibitor, and reassemble on washout
430. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31819277
     Structure of H3K36-methylated nucleosome-PWWP complex reveals multivalent cross-gyre binding.

     Wang H, Farnung L, et al. · Nat Struct Mol Biol 2020
     used by Does the fusion need the PWWP arm? An artificial CXXC + H3K36me2-reader + AF4-interaction protein substitutes for a whole MLL fusion - but LEDGF itself is not required for the fusion to reach chromatin, Menin and LEDGF hold WILD-TYPE KMT2A on chromatin; for the fusion LEDGF is functionally required but positionally dispensable, Plain-English: chromatin and epigenetics — the sticky notes on the DNA, and which ones matter here, PSIP1 keeps R-loops off the genes it sits on, and removing it causes transcription-replication conflict, DNA damage and PARP-inhibitor sensitivity, The third job: LEDGF sits on transcribed gene bodies with splicing factors and changes exon choice in half the genes that have alternative isoforms
431. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 32948771
     Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules.

     Nabet B, Ferguson FM, Seong BKA, Kuljanin M, et al. · Nat Commun 2020
     used by Does the fusion's programme fall apart in the same order in KMT2A::AFF1 as in MLL::AF9? The chain's only ordering measurement, repeated on the index fusion, Experiment: build the missing KMT2A::AFF1 degron and titrate it — what fractional occupancy does the program actually need?, Reversibility and kinetics — does the program collapse when the fusion is removed, and how fast?, Titrate PRC1.1 capacity against menin-inhibitor response, and measure H2AK119ub on the same timecourse as H3K79me2
432. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32228103
     The selenium-containing drug ebselen potently disrupts LEDGF/p75-HIV-1 integrase interaction by targeting LEDGF/p75.

     Zhang DW, Yan HL, et al. · J Enzyme Inhib Med Chem 2020
     used by Ebselen: the only small molecule reported to bind LEDGF itself - and it does it by making selenium-sulphur bonds with whatever thiols it meets
433. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     GSE149183 supplementary filelist.txt and SOFT family file (sample list as served 2026-09-23)

     Perner F, Gadrey JY, Xiong Y, et al. · NCBI Gene Expression Omnibus 2020
     used by Eighteen libraries, no replicate: what the only absolute-scale chromatin dataset in this project is structurally unable to say, and why this project's own floors may not be borrowed to fill the gap, Six to twenty-four libraries in RS4;11: two DOT1L inhibitors titrated to equal spike-in-measured global H3K79me2 loss, three replicates per arm, plus the no-primary control that no public deposit contains - the smallest experiment that would convert four moderate entries in this beat into testable ones, The only absolute-scale H3K79me2 deposit this project has contains no IgG or no-primary library, so the 1-31% residual measured after DOT1L inhibition cannot be separated from antibody background - the single cheapest missing control in the dataset
434. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 32296180
     Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

     Waszak SM, Robinson GW, et al. · Nature 2020
     used by ELP1 (IKBKAP/IKAP) - the Elongator scaffold that was first named for the IKK complex, is a paediatric-cancer predisposition gene, and has an RNA Pol II contact in IntAct, ELP5 (DERP6) - the bridge that joins ELP3 to ELP4, the most essential Elongator subunit in DepMap, and a gene whose cytoplasmic call rests on an overexpression experiment, ELP6 (TMEM103/C3orf75) - an Elongator subunit named after a membrane protein it is not, whose entire localisation record comes from a Drosophila paper its own symbol cannot retrieve
435. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31853060
     Impaired cell fate through gain-of-function mutations in a chromatin reader.

     Wan L, Chong S, Xuan F, Liang A, Cui X, Gates L, Carroll TS, Li Y, Feng L, Chen G, Wang SP, Ortiz MV · Nature 2020
     used by ENL's nuclear annotation has no citation at all, and every picture of ENL in a nucleus is of a mutant or a fusion, never the wild-type protein
436. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 33099470
     TIP60/P400/H4K12ac Plays a Role as a Heterochromatin Back-up Skeleton in Breast Cancer.

     Idrissou M, Boisnier T, Sanchez A, Khoufaf FZH, Penault-Llorca F, Bignon YJ, Bernard-Gallon D · Cancer Genomics Proteomics 2020
     used by EP400 - the ATPase that swaps H2A.Z in; its complex is required by MLL leukaemia stem cells, and in DepMap it is one of the three genes LEAST required in KMT2A-rearranged lines
437. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32708675
     VPS72/YL1-Mediated H2A.Z Deposition Is Required for Nuclear Reassembly after Mitosis.

     Moreno-Andrés D, Yokoyama H, Scheufen A, Holzer G, Lue H, Schellhaus AK, Weberruss M, Takagi M, Antonin W · Cells 2020
     used by EP400 - the ATPase that swaps H2A.Z in; its complex is required by MLL leukaemia stem cells, and in DepMap it is one of the three genes LEAST required in KMT2A-rearranged lines
438. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32209463
     Structural Basis for EPC1-Mediated Recruitment of MBTD1 into the NuA4/TIP60 Acetyltransferase Complex.

     Zhang H, Devoucoux M, Song X, Li L, et al. · Cell Rep 2020
     used by EPC1 - the NuA4/TIP60 subunit whose C-terminal fragment grips MBTD1, making it the contact a leukaemic fusion cannot do without and the mildest dependency in that whole complex, Low-grade endometrial stromal sarcoma is a family of NuA4-acetyltransferase-to-Polycomb fusions, and that is why one of MBTD1's two fusions looks nothing like the other, MBTD1 - the H4K20me1/me2 reader inside NuA4/TIP60, the quiescence brake on adult haematopoietic stem cells, and the 3' partner of ZMYND11::MBTD1 whose methyl-lysine cage the fusion carries and does not use, MBTD1 is the effector-recruiting half of a leukaemia fusion and the addressing half of a sarcoma fusion while donating nearly all of itself to both - so the junction, not the parts, assigns the role, MBTD1::EZHIP (MBTD1-CXorf67), t(X;17)(p11.2;q21.33) - MBTD1's other fusion, in which a NuA4 subunit delivers an H3K27M-mimicking PRC2 poison to low-grade endometrial stromal sarcoma, ZMYND11::MBTD1 is the KMT2A-fusion architecture assembled from different parts - and the part it throws away is a direct physical brake on KMT2A itself
439. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31838007
     Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials

     Doebele RC, Drilon A, Paz-Ares L, et al. · Lancet Oncology 2020
     used by ETV6::NTRK3 (ETV6-TRKC), t(12;15)(p13;q25), TRK inhibitors: one drug, seventeen cancers, and a paediatric population that actually got dosed
440. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31713622
     New developments on the Encyclopedia of DNA Elements (ENCODE) data portal.

     Luo Y, Hitz BC, Gabdank I, et al. · Nucleic Acids Research 2020
     used by Every peak file of all 13 ENCODE BRCA1, CBX3 and CBX1 experiments opened at the exon-11 element, not just the two Q37 reached: BRCA1 is there in BOTH pre-IDR replicates of THREE experiments - HeLa-S3, H1 and HepG2, global IDR 0.059, 0.577 and 0.482 - and it is a clean zero in both K562 experiments and in GM12878 against 300,000-peak pre-IDR lists, Measured in six ENCODE cell types against every conservative-IDR CTCF anchor of the same cell: the KMT2A exon-11 anchor sits at the 70.6th percentile of CTCF occupancy (range 28.2-81.8, fold over the anchor median 0.69-2.37) - a called peak in 6 of 6 cells and an ORDINARY one, which fails the instrument control the corpus pre-registration wrote for this very experiment, RUN, and the absence closes: all 13 released ENCODE BRCA1, CBX3 and CBX1 ChIP-seq tracks read at the KMT2A locus with three nulls - zero called peaks in 13 of 13, the breakpoint cluster at 0.57-1.24x the genome, and the exon-11 CTCF element BELOW the median CTCF anchor of its own cell type in 10 of 13
441. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32378810
     High incidence of RAS pathway mutations among sentinel genetic lesions of Korean pediatric BCR-ABL1-like acute lymphoblastic leukemia.

     Lee JW, Kim Y, Cho B, Kim S, Jang PS, Lee J, Cho H, Lee GD, Chung NG, Kim M · Cancer Med 2020
     used by EWSR1::ZNF384 - the same EWSR1 exon 7 fragment that drives Ewing sarcoma, fused instead to a zinc-finger protein, in B-ALL
442. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31932729
     Titrating gene expression using libraries of systematically attenuated CRISPR guide RNAs

     Jost M, Santos DA, Saunders RA, et al. · Nature Biotechnology 2020
     used by Experiment: combinatorial dose-titration of the HOXA9/MEIS1 program to find its minimal cut set, Fault trees, minimal cut sets and common-cause failure — reliability engineering on a buffered oncogenic program, Hypothesis: the fusion output program fails at a threshold on total cut-set suppression, so three nodes at 40% beat one node at 90%
443. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31541685
     Recombinant expression and purification of AF1q and its interaction with T-cell Factor 7.

     Khan N, Park J, Dean WL, Gray RD, Tse W, Lee D, et al. · Protein Expr Purif 2020
     used by Experiment: does AF1q self-associate, and does KMT2A::MLLT11 transform? The two measurements nobody has made on the 10th most common KMT2A fusion, MLLT11 / AF1q — a 90-residue protein with no chromatin domain and no oligomerisation module, KMT2A partner in t(1;11)(q21;q23)
444. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32066721
     FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML.

     Sheng Y, et al. · Nat Commun 2020
     used by FOXM1 - a one-panel MEN1 co-IP from a 4,119-row atlas, attached to a protein that is independently a validated MLL-rearranged leukaemia stem-cell dependency, Hypothesis: menin-inhibitor sensitivity falls with cell-cycle exit, so the compartment that causes relapse is the one the drug reaches least — and nobody has sorted by cycle state to check, Quiescence (G0) — the state 15 entries invoke to explain measurable residual disease, defined here for the first time, Sort KMT2A-rearranged blasts by cell-cycle state, then measure menin-inhibitor response — the one-week experiment nobody has run
445. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33211010
     Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3.

     Finogenova K, Bonnet J, Poepsel S, Schäfer IB, Finkl K, Schmid K, et al. · Elife 2020
     used by H3K27me3 - the repressive mark this graph argued about for seventy-seven cycles without ever writing an entry for it, H3K36me2/3 - the mark that physically switches PRC2 off, that LEDGF reads to reach chromatin, and that a comparator fusion uses to keep EZH2 off HOXA, H3K4me3 - the mark KMT2A's own SET domain writes, that the fusion cannot write, that an interface in this graph already binds, and that switches PRC2 off, PRC2 - the complex, not the subunit, is the unit every experiment in this disease actually resolves, Trithorax against Polycomb at HOXA: the textbook antagonism, and the two ways this disease breaks it
446. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33054052
     SETDB1 mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukemic transformation.

     Ropa J; Saha N; Hu H; Peterson LF; Talpaz M; Muntean AG · Haematologica 2020
     used by H3K9me3 - measured in KMT2A::AFF1 cells, in a supplementary figure, and it rises GENERALLY where H3K27ac falls SPECIFICALLY in the same experiment, SETDB1 (Q15047, KMT1E/ESET) - the second H3K9me3 writer: it represses the fusion's own targets via the PAF1 complex, it is required in fetal liver HSPCs and in leukaemic stem cells, and it is a broad dependency in half the CRISPR panel - three published directions that do not agree, UNC0642 - the G9a/GLP chemical probe that abolished doxorubicin-induced Kmt2a copy gain in mice, and the one intervention in this beat that has been given to an animal
447. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33037410
     SUV39H1 regulates the progression of MLL-AF9-induced acute myeloid leukemia.

     Chu Y; Chen Y; Guo H; Li M; Wang B; Shi D; et al. · Oncogene 2020
     used by H3K9me3 - measured in KMT2A::AFF1 cells, in a supplementary figure, and it rises GENERALLY where H3K27ac falls SPECIFICALLY in the same experiment, SUV39H1 (O43463, KMT1A) - the H3K9me3 writer: a menin effector whose binding region OVERLAPS the drug pocket at its N-terminus, a tumour suppressor in MLL-AF9 AML, recruited to double-strand breaks by CTCF, and never localised at the KMT2A locus in any cell type
448. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.journal-articlePMID 32615502
     PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia

     Gawel JM, Shouksmith AE, Raouf YS, Nawar N, Toutah K, Bukhari S, Manaswiyoungkul P, Olaoye OO, Israelian J, Radu TB, Cabral AD, Sina D, Sedighi A, de Araujo ED, Gunning PT · Eur J Med Chem 201:112411 2020
     used by HDAC6 - the one HDAC family member this graph refused, whose refusal named a falsifier that has been in the literature since 2020 and fires in the index fusion's own cell line, Testing this corpus's own recorded refusals instead of its gap list overturned the first refusal tried, and the refusal had named the falsifier itself
449. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33268767
     Long noncoding RNA HOXA-AS2 functions as an oncogene by binding to EZH2 and suppressing LATS2 in acute myeloid leukemia (AML)

     Feng Y, Hu S, Li L, Peng X, Chen F · Cell Death & Disease 11(12):1025 2020
     used by HOXA-AS2 and HOXA-AS3 — mid-cluster antisense transcripts with essentially no KMT2A-r evidence, The unnamed AML lines are NB4 and THP-1 - and NB4 is not KMT2A-rearranged at all
450. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32128251
     Structural and functional insight into the effect of AFF4 dimerization on activation of HIV-1 proviral transcription

     Tang D, Chen C, Liao G, Liu J, Liao B, Huang Q, Chen K, Feng J, Zhu Z, Teng M, Niu L, Zhang J, Zhu C · Cell Discovery 2020
     used by Hypothesis — forced-oligomerisation interfaces are the mutation-resistant drug targets the fusion field has been ignoring, Separation-of-function test: does KMT2A::AFF1 need its C-terminal homology domain to dimerise?, The AFF-family N-terminus on cyclin T1: Kd 10 nM, a 2.94 A crystal, and every number in it measured on AFF4 rather than on AFF1
451. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32001657
     Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia

     Uckelmann HJ, Kim SM, Wong EM, et al. · Science 2020
     used by Hypothesis — the menin lesson generalises: every non-enzymatic fusion has an obligate partner interface that is more druggable than the fusion, NPM1 (nucleophosmin) — the nucleolar shuttle whose mutant form binds chromatin with KMT2A and buys the second menin-inhibitor indication, NUP98 fusions share the menin dependency (confirmed preclinically) — and the partner-supplied reader/writer module is not why, The platform argument's best evidence: one drug, two genotypes, one interface
452. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32216001
     Gene rearrangements of MLL and RUNX1 sporadically occur in normal CD34+ cells under cytokine stimulation

     Harada Y, Shingai N, Ding Y, et al. · Cancer science 2020
     used by Hypothesis: the KMT2A break can be prevented rather than the fusion treated - stated so it can be killed, and it probably should be, The test bed nobody names: KMT2A rearrangement can be induced and counted in primary human CD34+ and fetal liver stem cells, and it happens without any drug at all
453. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31768017
     RNA-binding protein IGF2BP1 maintains leukemia stem cell properties by regulating HOXB4, MYB, and ALDH1A1

     Elcheva IA, et al. · Leukemia 2020
     used by IGF2BP1 — the IMP paralogue that belongs to a DIFFERENT fusion, and the cleanest control the family offers
454. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32814053
     Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

     Haenig C, Atias N, Taylor AK, et al. (25 authors; senior author Wanker EE) · Cell Rep 2020
     used by IntAct curates 47 interactions against engineered MLL fusion proteins, and every accession-keyed query in this project is blind to all of them - while its PSICQUIC mirror stops at 2024
455. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31271662
     Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells.

     Xu X; Wang L; Hu L; Dirks WG; Zhao Y; Wei Z; Chen D; Li Z; Wang Z; Han Y; et al. · Int J Cancer 2020
     used by JDI-12 - published as a JMJD1C inhibitor that preferentially kills KMT2A-rearranged leukaemia and spares cord blood, then used as 'KDM3i' to CREATE KMT2A rearrangements in cord-blood progenitors, by two papers that do not cite each other, JMJD1C / KDM3C - named in three entries of this graph as one of the only loci that loses fusion occupancy under a menin inhibitor, ranked 23rd of 17,728 for KMT2A-selective dependency in this project's own scan, with the strongest published shRNA effect in SEM - and no entry until now, KDM3B - the H3K9me1/2 demethylase that sits on the KMT2A breakpoint cluster region and keeps it from rearranging, and the only leukaemia gene in this graph whose direction of effect flips between the myeloid and the lymphoid literature, One demethylase family sits at both ends of this disease - KDM3B gates whether KMT2A rearranges, JMJD1C is what the resulting fusion needs to survive - and a single compound hits both, so its therapeutic index runs in opposite directions in the two cell populations it reaches
456. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32017785
     Jmjd1c is dispensable for healthy adult hematopoiesis and Jak2V617F-driven myeloproliferative disease initiation in mice.

     Staehle HF; Heinemann J; Gruender A; Omlor AM; Pahl HL; Jutzi JS · PLoS One 2020
     used by JMJD1C / KDM3C - named in three entries of this graph as one of the only loci that loses fusion occupancy under a menin inhibitor, ranked 23rd of 17,728 for KMT2A-selective dependency in this project's own scan, with the strongest published shRNA effect in SEM - and no entry until now
457. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33155839
     Nuclear Localization Is Not Required for Tip60 Tumor Suppressor Activity in Breast and Lung Cancer Cells.

     Ravichandran P, et al. · DNA Cell Biol 2020;39:2077-2084 2020
     used by KAT5 / Tip60 - the acetyltransferase in the only direct KMT2A-fusion histone-variant result, and both fusions tested were myeloid
458. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32542325
     Lysine acetyltransferase Tip60 is required for hematopoietic stem cell maintenance.

     Numata A, Kwok HS, Zhou QL, Li J, Tirado-Magallanes R, Angarica VE, Hannah R, Park J, Wang CQ, Krishnan V, Rajagopalan D, Zhang Y, Zhou S, Welner RS, Osato M, Jha S, Bohlander SK, Göttgens B, Yang H, Benoukraf T, Lough JW, Bararia D, Tenen DG · Blood 2020
     used by KAT5 / Tip60 - the acetyltransferase in the only direct KMT2A-fusion histone-variant result, and both fusions tested were myeloid
459. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31827282
     HBO1 is required for the maintenance of leukaemia stem cells

     MacPherson L, Anokye J, Yeung MM, et al. · Nature 2020
     used by KAT7 / HBO1 — an enzyme, a leukaemia-stem-cell dependency, and an inhibitor already in a crystal, Phase-2 dossier: KAT7/HBO1 - the only enzyme here with a real active site, a co-crystal inhibitor and a co-dependency that survives lineage adjustment almost intact
460. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32634241
     Specific patterns of H3K79 methylation influence genetic interaction of oncogenes in AML

     Kingsley MC, ... Bernt KM · Blood Advances 2020
     used by Kathrin Bernt (University of Pennsylvania / Children's Hospital of Philadelphia) — DOT1L and H3K79 methylation in KMT2A-rearranged leukemia
461. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 32901907
     Combined expression levels of KDM2A and KDM2B correlate with nucleolar size and prognosis in primary breast carcinomas.

     De Nicola I, Guerrieri AN, et al. · Histol Histopathol 2020
     used by KDM2A - the CXXC reader that antagonises KMT2A leukaemogenesis, and displaces wild-type MLL rather than the fusion, Three CXXC-pathway activities converge on rDNA - KDM2B represses Pol I, KMT2A and SETD1A bind the whole locus, MLL-AF4 is predominantly nucleolar - and no paper contains two of them
462. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32402251
     Leukemogenic Chromatin Alterations Promote AML Leukemia Stem Cells via a KDM4C-ALKBH5-AXL Signaling Axis.

     Wang J, Li Y, Wang P, Han G, Zhang T, Chang J, Yin R, Shan Y, Wen J, Xie X, Feng M, Wang Q, Hu J, Cheng Y, Zhang T, Li Y, Gao Z, Guo C, Wang J, Liang J, Cui M, Gao K, Chai J, Liu W, Cheng H, Li L, Zhou F, Liu L, Luo Y, Li S, Zhang H · Cell Stem Cell 2020
     used by KDM4C (JMJD2C/GASC1) — recruited by the retained KMT2A N-terminus, drugged in a KMT2A::AFF1 line, and invisible to CRISPR
463. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32196814
     Cryptic and atypical KMT2A-USP2 and KMT2A-USP8 rearrangements identified by mate pair sequencing in infant and childhood leukemia.

     Blackburn PR, Smadbeck JB, Znoyko I, Webley MR, Pitel BA, Vasmatzis G, Xu X, Greipp PT, Hoppman NL, Ketterling RP, Baughn LB, Lindsey KG, Schandl CA, Wolff DJ, Peterson JF · Genes, Chromosomes & Cancer 2020
     used by KMT2A::USP2 is invisible to karyotype and often to FISH, so these patients are misclassified as fusion-negative, KMT2A::USP2, inv(11)(q23.3q23.3) - the minor-BCR fusion that keeps the PHD fingers, KMT2A::USP8, t(11;15)(q23;q21) - three patients, and the second instance of a deubiquitinase partner, Menin inhibitors are prescribed on 'KMT2A-rearranged', a category that contains proteins as different as KMT2A::AFF1 and KMT2A::USP2, USP8 (UBPY) - the second deubiquitinase KMT2A partner, three patients, same UCH logic
464. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33169020
     MLL4-associated condensates counterbalance Polycomb-mediated nuclear mechanical stress in Kabuki syndrome.

     · Nat Genet 2020
     used by KMT2D (MLL2/MLL4) - the gene named in this graph's menin-resistance entry, written here for the first time
465. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32851167
     Gliotoxin, identified from a screen of fungal metabolites, disrupts 7SK snRNP, releases P-TEFb, and reverses HIV-1 latency

     Stoszko M, Al-Hatmi AMS, Skriba A, Roling M, Ne E, Crespo R, et al., Mahmoudi T · Science Advances 6(33):eaba6617 2020
     used by LARP7's measured readout is P-TEFb release and Pol II CTD Ser2 phosphorylation, not a histone mark - and the one compound shown to act through it disrupts the particle rather than the protein
466. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 32876512
     Aberrant leukemia-associated immunophenotype as potential harbinger of lineage switch in KMT2A-rearranged leukemia: a case series.

     Yost CM, ..., Schafer ES · Leuk Lymphoma 2020
     used by Lineage drift - the partial state between B-ALL and AML, and the fact that nobody has published the ORDER in which markers change, Which marker moves first? A re-analysis of flow files that already exist, to put an order on lineage switch
467. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33052756
     First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia

     Salamero O, Montesinos P, Willekens C, et al. · Journal of Clinical Oncology 2020
     used by LSD1/KDM1A inhibition — a differentiation therapy with real clinical pharmacodynamics and no randomised proof, The only two trials stopped on a stated risk-benefit judgement are GSK2879552 (LSD1) studies in AML, while iadademstat, another LSD1 inhibitor, ran a KMT2A-rearranged-enriched expansion with an acceptable safety profile - so the stop looks molecule-specific, and its reason is unread
468. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32496561
     LUZP1 and the tumor suppressor EPLIN modulate actin stability to restrict primary cilia formation.

     Gonçalves J, Sharma A, Coyaud É, Laurent EMN, Raught B, Pelletier L · J Cell Biol 2020
     used by LUZP1 / fimbacin (Q86V48) - the weakest index-fusion call of the nine, and the strongest non-index call: p = 0.127 against MLL-AF4 and 2.6e-10 against MLL-ENL
469. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32409666
     Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response.

     Szewczyk MM, Ishikawa Y, Organ S, Sakai N, et al. · Nat Commun 2020
     used by Measure H3R2 and H4R3 methylation states at KMT2A-fusion targets by isomer-resolving mass spectrometry, and test the gate by writer perturbation read out on the enzyme's product - the experiment that has never been done in any fusion, PRMT7 - the enzyme whose class is still disputed, which represses a KMT2 enzyme by writing H4R3me2s, which is required for leukaemia stem cells in CML, and whose only H3R2 claim is the one this beat was dispatched to check
470. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32971831
     Menin and Menin-Associated Proteins Coregulate Cancer Energy Metabolism

     Chou CW, Tan X, Hung CN, Lieberman B, Chen M, Kusi M, Mitsuya K, Lin CL, Morita M, Liu Z, Chen CL, Huang TH · Cancers (Basel) 12(9):2715 2020
     used by MED12 - a named menin-associated protein that restrains menin's transcriptional output, and the anchor of the CDK8 module a KMT2A-r AML paper co-targets
471. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32102997
     The role of Mediator and Little Elongation Complex in transcription termination.

     Takahashi H, Ranjan A, Chen S, Suzuki H, Shibata M, Hirose T, Hirose H, Sasaki K, Abe R, Chen K, He Y, Zhang Y, Takigawa I, Tsukiyama T, Watanabe M, Fujii S, Iida M, Yamamoto J, Yamaguchi Y, Suzuki Y, Aoto Y, Tanaka H, Sugiyama S, Kanemaki MT, Ohkawa Y, Conaway JW, Conaway RC, Hatakeyama S · Nat Commun 2020
     used by MED26 — a common-essential Mediator subunit with a solved 87-residue domain and no ChEMBL target entity at all
472. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32913188
     A small molecular compound CC1007 induces cross-lineage differentiation by inhibiting HDAC7 expression and HDAC7/MEF2C interaction in BCR-ABL1- pre-B-ALL.

     Wang Z, Zhang Y, Zhu S, et al. · Cell Death Dis 2020
     used by MEF2C — an output-program transcription factor, the second-strongest leukemia co-dependency, and a gene humans cannot spare one copy of
473. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32223036
     Mixed phenotype acute leukemia: Biological profile, clinical characteristic and treatment outcomes: Report of the population-based study

     Zajac-Spychala O, Irga-Jaworska N, Drozynska E, Muszynska-Roslan K, Krawczuk-Rybak M, et al. · European Journal of Haematology 2020
     used by Mixed-phenotype acute leukemia and KMT2A rearrangement — plasticity caught in the act
474. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31661160
     Mixed-phenotype acute leukemia: A cohort and consensus research strategy from the Children's Oncology Group Acute Leukemia of Ambiguous Lineage Task Force

     Orgel E, Alexander TB, Wood BL, Kahwash SB, Devidas M, et al. · Cancer 2020
     used by Mixed-phenotype acute leukemia and KMT2A rearrangement — plasticity caught in the act
475. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32297416
     Concordance among hematopathologists in classifying blasts plus promonocytes: A bone marrow pathology group study

     Foucar K, Hsi ED, Wang SA, Rogers HJ, Hasserjian RP, Bagg A, et al., Bueso-Ramos CE · International Journal of Laboratory Hematology 2020
     used by Monoblast — the immature monocyte that names FAB M5a, the dominant morphology of congenital KMT2A leukaemia
476. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32040550
     Myc-Miz1 signaling promotes self-renewal of leukemia stem cells by repressing Cebpα and Cebpδ.

     Zhang L; Li J; Xu H; Shao X; Fu L; Hou Y; Hao C; Li W; Joshi K; Wei W; Xu Y; Zhang F; Dai S; Breslin P; Zhang J; Zhang J · Blood 2020
     used by MYC - named in a hundred entries of this graph and, until now, written in none
477. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32966766
     Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy

     Forte D, Garcia-Fernandez M, Sanchez-Aguilera A, Stavropoulou V, Fielding C, Martin-Perez D, Lopez JA, Costa ASH, et al. · Cell Metabolism 2020
     used by Nestin+ mesenchymal stem cell — the niche cell that MLL-AF9 leukaemia wakes up and then loses, Niche-mediated chemoprotection in KMT2A-rearranged leukaemia — real for cytarabine, unsupported for menin inhibitors, and the one hypoxia experiment points the other way
478. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 32154134
     Mutations predictive of hyperactive Ras signaling correlate with inferior survival across high-risk pediatric acute leukemia.

     Ney GM, Anderson B, Bender J, et al. · Translational Pediatrics 2020
     used by NF1 - the only tumour-suppressor loss in this disease, and it is a deletion, so a mutation panel cannot see it, PTPN11/SHP2 - non-recurrent in infant KMT2A-rearranged ALL, well drugged everywhere else, and the one leukaemia trial that carried a SHP2 inhibitor was withdrawn
479. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 32141887
     A Novel SS18-SSX Fusion-specific Antibody for the Diagnosis of Synovial Sarcoma.

     Baranov E, McBride MJ, Bellizzi AM, et al. · Am J Surg Pathol 2020
     used by No junction-specific antibody exists for any KMT2A fusion - and synovial sarcoma shows exactly what one would buy
480. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32333633
     Evaluation of VTP-50469, a menin-MLL1 inhibitor, against Ewing sarcoma xenograft models by the pediatric preclinical testing consortium.

     Kurmasheva RT, Bandyopadhyay A, Favours E, et al. · Pediatr Blood Cancer 2020
     used by No menin inhibitor has ever enrolled a KMT2A-rearranged solid tumour, and the one solid-tumour menin trial that read out was terminated for lack of efficacy, The predictable clinical error this beat exists to prevent: a menin inhibitor given for a KMT2A-rearranged sarcoma because of the gene name
481. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 33029857
     Histone H3K79 demethylation by KDM2B facilitates proper DNA replication through PCNA dissociation from chromatin.

     Kang JY, Park JW, Hahm JY, et al. · Cell Prolif 2020
     used by Nobody has convincingly found the H3K79 eraser - and that constraint sets the clock on every DOT1L inhibitor
482. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 32792914
     Mixed Lineage Leukemia 1 Promoted Neuron Apoptosis in Ischemic Penumbra via Regulating ASK-1/TNF-α Complex.

     Feng Z, et al. · Front Neuroanat 2020
     used by Nobody has ever shown 14-3-3 binding directly to KMT2A: five records across every paralogue alias, and one of them is about AF4
483. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
     ENCODE Project GRCh38 fold-change-over-control bigWig files ENCFF734CUT and ENCFF800WUV (CTCF, GM12878, experiments ENCSR000AKB and ENCSR000DKV) and ENCFF571ZJJ (RAD21, GM12878, ENCSR000EAC), read over HTTP range requests with pybigtools 0.3.0 on 2026-09-22; file selection by the ENCODE portal search API

     ENCODE Project Consortium · ENCODE Portal 2020
     used by Not one of the four studies in this dispute measured CTCF or cohesin occupancy in a human blood cell - so this beat read ENCODE instead, and the element is a STRONGER CTCF site in a B-lymphoblastoid line than in HCT116, with the summit at the same base
484. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 32987765
     Prognostic Factors in Childhood Anaplastic Large Cell Lymphoma: Long Term Results of the International ALCL99 Trial

     Mussolin L, Le Deley MC, Carraro E, et al. · Cancers 2020
     used by NPM1::ALK (NPM-ALK), t(2;5)(p23;q35)
485. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 32766874
     Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies

     Michmerhuizen NL, Klco JM, Mullighan CG · Blood 2020
     used by NUP98 — domain architecture and residue coordinates (with the 1817/920 numbering trap resolved)
486. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 32179410
     Down-regulation of lncRNA NEAT1 regulated by miR-194-5p/DNMT3A facilitates acute myeloid leukemia

     Duan MY, Li M, Tian H, Tang G, Yang YC, Peng NC · Blood Cells, Molecules and Diseases 2020
     used by Paraspeckles and NEAT1 — no KMT2A evidence at all, but a fusion oncoprotein in another leukemia uses NEAT1 as a differentiation brake
487. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32698374
     Inhibition of Methyltransferase DOT1L Sensitizes to Sorafenib Treatment AML Cells Irrespective of MLL-Rearrangements: A Novel Therapeutic Strategy for Pediatric AML

     Lonetti A, Indio V, Laginestra MA, et al. · Cancers (Basel) 2020
     used by Pinometostat (EPZ-5676) — the DOT1L inhibitor, and the most instructive failure in this field
488. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33193587
     Validations of Top and Novel Susceptibility Variants in All-Age Chinese Patients With Acute Lymphoblastic Leukemia.

     Liao F, Ye Y, Yin D, et al. (15 authors; senior author Lu X) · Front Genet 2020
     used by PIP4K2A - the lipid kinase at a genome-wide childhood-ALL susceptibility locus, whose product is the ligand a PHD finger reads
489. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 32664515
     Mapping the Interactome of the Nuclear Heparan Sulfate Proteoglycan Syndecan-1 in Mesothelioma Cells.

     Kumar-Singh A, Shrinet J, Parniewska MM, Fuxe J, Dobra K, Hjerpe A · Biomolecules 2020
     used by PSIP1-SDC1 - DECLINED as an interaction, kept for the splicing thread: nuclear syndecan-1 co-IP in a mesothelioma line recovers LEDGF among an RNA-splicing-enriched network
490. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32285100
     Loss of RBBP4 results in defective inner cell mass, severe apoptosis, hyperacetylated histones and preimplantation lethality in mice†.

     Miao X, Sun T, Barletta H, Mager J, Cui W · Biol Reprod 2020
     used by RBBP4 - the shared histone-binding subunit that every leukaemia line needs, and whose identical-length paralogue cannot replace it
491. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31855575
     Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia.

     Klossowski S, Miao H, Kempinska K, et al. · J Clin Invest 2020
     used by Risk: the class's pharmacodynamic logic measures menin and reports it as the fusion, in a drug class dosed in infants, Where does the fusion go when menin inhibition evicts it? Almost nobody has looked - the published readouts are chromatin occupancy, the one protein whose fate was measured properly is menin, and the single human observation of fusion loss is confounded by a lineage switch
492. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 32541898
     Structure of complete Pol II-DSIF-PAF-SPT6 transcription complex reveals RTF1 allosteric activation.

     Vos SM, et al. · Nat Struct Mol Biol 2020;27:668-677 2020
     used by RTF1 — the PAF1C subunit the graph was missing, on a complex that does bind the retained KMT2A fragment, SUPT6H (SPT6) - the histone chaperone that rides with RNA polymerase II, which puts it closer to the fusion's proposed mechanism than anything else in this beat
493. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32539815
     Allogeneic hematopoietic stem cell transplantation can improve the prognosis of high-risk pediatric t(8;21) acute myeloid leukemia in first remission based on MRD-guided treatment

     Hu GH, Cheng YF, Lu AD, Wang Y, Zuo YX, Yan CH, Wu J, Sun YQ, Suo P, Chen YH, Chen H, Jia YP, Liu KY, Han W, Xu LP, Zhang LP, Huang XJ · BMC Cancer 2020
     used by RUNX1::RUNX1T1 (AML1-ETO), t(8;21)(q22;q22)
494. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32398749
     MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia.

     Itskovich SS, Gurunathan A, Clark J, Burwinkel M, Wunderlich M, Berger MR, Kulkarni A, Chetal K, Venkatasubramanian M, Salomonis N, Kumar AR, Lee LH · Nat Commun 2020
     used by SCAF11 / SRrp129 (Q99590) - an SR-related protein that binds the RNA Pol II CTD, in the pan-MLL-fusion core, and alone among the SCAF family, WBP11 (Q9Y2W2) - a splicing activator in the pan-MLL-fusion core, isolated from its own partners, and a human haploinsufficiency gene
495. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32341362
     Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance

     Barbier V, Erbani J, Fiveash C, et al. · Nat Commun 2020
     used by SELE (E-selectin) - the vascular-niche chemoresistance receptor with a clinical antagonist, zero KMT2A papers, and a paediatric trial that a company restructuring closed
496. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32664447
     Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach.

     Mendes A, et al. · Cells 2020
     used by SET::NUP214 recruits DOT1L by a different surface from CALM-AF10 and KMT2A::MLLT10: the founding paper tested for AF10 in the complex and did not find it, The fusion-oncoprotein TurboID experiment this graph proposes has already been published - for PML::RARA, RUNX1::RUNX1T1, CBFB::MYH11, NUP98::HOXA9 and SET::NUP214, and not for any KMT2A fusion, Where SET::NUP214 actually is: mobile intranuclear bodies that trap CRM1, dissolve in mitosis and under CRM1 inhibitor, and reassemble on washout
497. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33106467
     Neonatal Acute Lymphoblastic Leukemia with t(9;11) Translocation Presenting as Blueberry Muffin Baby: Successful Treatment by ALL-BFM Induction Therapy, Allogeneic Stem Cell Transplantation from an Unrelated Donor, and PCR-MRD-Guided Post-Transplant Follow-Up

     Schlegel S, Hamm H, Reichel A, et al. · American Journal of Case Reports 2020
     used by Skin first, blood later: a three-day-old referred for purple spots, with KMT2A::MLLT3 neonatal ALL
498. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33095160
     SON and SRRM2 are essential for nuclear speckle formation.

     Ilik IA, Malszycki M, Lubke AK, Schade C, Meierhofer D, Aktas T · eLife 2020
     used by SON (P18583) - a nuclear speckle scaffold that BINDS MENIN and inhibits MLL complex assembly, and the one protein in this tranche the Skucha authors name in their own discussion
499. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32025035
     SPEN integrates transcriptional and epigenetic control of X-inactivation

     Dossin F, Pinheiro I, Zylicz JJ, Roensch J, Collombet S, Le Saux A, Chelmicki T, Attia M, Kapoor V, Zhan Y, Dingli F, Loew D, Mercher T, Dekker J, Heard E · Nature 578(7795):455-460 2020
     used by SPEN is the only member of the real-gap floor whose epigenetic readout is direct and published: its SPOC domain recruits NCoR/SMRT, NuRD and the m6A machinery to active enhancers and promoters, and it disengages from chromatin the moment silencing succeeds
500. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32114371
     Osteopontin-c is overexpressed in KMT2A-AFF1 positive pediatric B-cell lymphoblastic leukemia when compared to those with ETV6-RUNX1

     da Fonseca Bastos ACS, da Silva Rezende AC, Ferreira LB, et al. · Leuk Res 2020
     used by SPP1 (osteopontin) - the endosteal matrix protein whose knockdown prolongs survival in MLL-AF9 mice, and the one KMT2A::AFF1-specific paper about it cannot be read
501. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32997997
     Activation of CpG-Rich Promoters Mediated by MLL Drives MOZ-Rearranged Leukemia

     Miyamoto R, Okuda H, Kanai A, et al. (Yokoyama A, senior author) · Cell Reports 32(13):108200 2020
     used by Step 1 — How the fusion finds its genes: AT-hooks and the CXXC domain reading unmethylated CpG
502. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32522980
     Spt6 is a maintenance factor for centromeric CENP-A.

     Bobkov GOM, Huang A, van den Berg SJW, et al. · Nature Communications 2020
     used by SUPT6H (SPT6) - the histone chaperone that rides with RNA polymerase II, which puts it closer to the fusion's proposed mechanism than anything else in this beat
503. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33035457
     Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial.

     Morschhauser F, Tilly H, Chaidos A, McKay P, Phillips T, Assouline S, et al. · Lancet Oncol 2020
     used by Tazemetostat - an approved EZH2 inhibitor, and the drug this disease's own biology predicts will not work
504. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33328229
     S-adenosyl-l-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling

     Greco CM, Cervantes M, Fustin JM, Ito K, Ceglia N, Samad M, Shi J, Koronowski KB, et al. · Science Advances 2020
     used by The blind spot is closed: all four K1130-and-leukaemia full-text hits are reviews restating the source paper, and the citation-network bound survives 26 nomenclatures rather than five
505. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32326074
     Lifetime Costs of Surviving Cancer-A Queensland Study (COS-Q): Protocol of a Large Healthcare Data Linkage Study

     Merollini KMD, Gordon LG, Aitken JF, Kimlin MG · International Journal of Environmental Research and Public Health 2020
     used by The cost of surviving: late effects carry a lifetime bill nobody has costed for infants
506. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 32826896
     Taf14 recognizes a common motif in transcriptional machineries and facilitates their clustering by phase separation

     Chen G, Wang D, Wu B, Yan F, Xue H, Wang Q, Quan S, Chen Y · Nature Communications 2020
     used by The strongest published case that condensates are load-bearing in KMT2A-fusion leukemia — and it is AKAP95, not AFF1
507. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31840362
     Skin toxicity following treosulfan-thiotepa-fludarabine-based conditioning regimen in non-malignant pediatric patients undergoing hematopoietic stem cell transplantation.

     Even-Or E, Altman Kohl S, Zaidman I, Stepensky P, Molho-Pessach V · Pediatric Transplantation 2020
     used by Thiotepa - the third agent that reaches the central nervous system completely, and whose alkylating metabolites are excreted through the skin into a nappy
508. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31701524
     Proposed Therapeutic Range of Treosulfan in Reduced Toxicity Pediatric Allogeneic Hematopoietic Stem Cell Transplant Conditioning: Results From a Prospective Trial.

     Chiesa R, Standing JF, Winter R, Nademi Z, Chu J, Pinner D, Kloprogge F, McLellen S, et al. · Clinical Pharmacology and Therapeutics 2020
     used by Treosulfan - a European conditioning standard for three decades that the FDA first approved in January 2025, for a diagnosis and an age that exclude the infant with KMT2A-rearranged ALL
509. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31114027
     UBAP2L arginine methylation by PRMT1 modulates stress granule assembly.

     Huang C, Chen Y, Dai H, Zhang H, Xie M, et al. · Cell Death Differ 2020
     used by UBAP2L (Q14157) - a BMI1-interacting protein essential for haematopoietic stem cell activity, in the pan-MLL-fusion core, and a stress-granule nucleator recovered from NUCLEAR lysate
510. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 32415735
     Refinement of the clinical and mutational spectrum of UBE2A deficiency syndrome.

     Cordeddu V, Macke EL, Radio FC, Lo Cicero S, Pantaleoni F, Tatti M, Bellacchio E, Ciolfi A, Agolini E, Bruselles A, Brunetti-Pierri N, Suri M, Josephs KS, McEntagart M, Lanpher B, et al. · Clin Genet 2020
     used by UBE2A (RAD6A) — the E2 for H2B ubiquitination in one primary account, contradicted by another, and with no KMT2A literature at all
511. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 32678895
     Iron chelation rescues hemolytic anemia and skin photosensitivity in congenital erythropoietic porphyria

     Blouin JM, Ged C, Lalanne M, Lamrissi-Garcia I, Morice-Picard F, Costet P, Daher R, Moreau-Gaudry F, Bedel A, Puy H, Gouya L, Karim Z, Richard E · Blood 136:2457-2468 2020
     used by UROS: searched and empty — the scan's rank-15 hit has no leukemia literature, and no entry was written
512. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32171069
     Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study

     Karol SE, Alexander TB, Budhraja A, et al. · Lancet Oncology 2020
     used by Venetoclax in KMT2A-rearranged leukemia — the apoptotic partner every other drug needs
513. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31874114
     WBP11 is required for splicing the TUBGCP6 pre-mRNA to promote centriole duplication.

     Park EM, Scott PM, Clutario K, Cassidy KB, Zhan K, Gerber SA, Holland AJ · J Cell Biol 2020
     used by WBP11 (Q9Y2W2) - a splicing activator in the pan-MLL-fusion core, isolated from its own partners, and a human haploinsufficiency gene
514. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33276377
     Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice.

     Martin EMMA, Enriquez A, Sparrow DB, Humphreys DT, McInerney-Leo AM, et al. · Hum Mol Genet 2020
     used by WBP11 (Q9Y2W2) - a splicing activator in the pan-MLL-fusion core, isolated from its own partners, and a human haploinsufficiency gene
515. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 32541063
     The 3' processing of antisense RNAs physically links to chromatin-based transcriptional control.

     Fang X, Wu Z, Raitskin O, Webb K, Voigt P, Lu T, Howard M, Dean C · Proc Natl Acad Sci U S A 2020
     used by WDR33 (Q9C0J8) - the subunit that reads AAUAAA, in the pan-MLL-fusion core, and the plant homolog of which physically links 3' processing to H3K4 demethylation
516. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32589365
     Hyperglycemia requiring insulin during acute lymphoblastic leukemia induction chemotherapy is associated with increased adverse outcomes and healthcare costs.

     McCormick MC, Sharp E, Kalpatthi R, et al. · Pediatric Blood & Cancer 2020
     used by What it costs to treat a child through frontline leukemia therapy
517. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 33109678
     What are the volume and budget needs to provide chemotherapy to all children with acute lymphoblastic leukaemia in Thailand? Development and application of an estimation tool

     Sruamsiri R, Ferrario A, Ross-Degnan D, et al. · BMJ Open 2020
     used by What it costs to treat a child through frontline leukemia therapy
518. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 33139954
     Genome-wide detection of DNA double-strand breaks by in-suspension BLISS

     Bouwman BAM, Agostini F, Garnerone S, et al. · Nature protocols 2020
     used by What maps a DNA break, and the fact that none of the modern instruments has ever been pointed at KMT2A in a blood progenitor
519. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 33327558
     A Novel Platform to Test In Vivo Single Gene Dependencies in t(8,21) and t(15,17) AML Confirms Zeb2 as Leukemia Target

     De Conti G, Gruszka AM, Valli D, Cammarata AU, Righi M, Mazza M, Pelicci PG · Cancers (Basel) 12:3768 2020
     used by ZEB2 — an EMT transcription factor that turns out to be a leukemia dependency and a guardian of lineage fidelity
520. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 32274925
     Arsenite Exposure Displaces Zinc from ZRANB2 Leading to Altered Splicing.

     Banerjee M, et al. · Chem Res Toxicol 2020
     used by ZRANB2 - the only bait in any published proximity experiment that reaches AFF1, AFF4, ELL, MLLT1, CCNT1, KMT2A and DOT1L at once
521. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31493143
     Crosstalk between 14-3-3θ and AF4 enhances MLL-AF4 activity and promotes leukemia cell proliferation.

     Fioretti T, et al. · Cell Oncol (Dordr) 2019
     used by 14-3-3 theta binds AF4 at Ser588 and rides into the MLL-AF4 complex - the phospho-gated contact the fusion really does carry, KMT2A is a 14-3-3 client by proxy: the contact is on an AFF-family scaffold, not on KMT2A, Nobody has ever shown 14-3-3 binding directly to KMT2A: five records across every paralogue alias, and one of them is about AF4, One immunoprecipitation that decides whether 14-3-3 touches KMT2A at all
522. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     GSE127507 per-sample SOFT records, 26 samples, 134,259 characters, fetched live 2026-09-23

     · NCBI GEO 2019
     used by A ChIP-seq series of 158 samples that names no antibody anywhere in its metadata: the string 'antibod' occurs ZERO times in GSE260742's 419,824-character SOFT dump, and the reagents are in a supplementary spreadsheet the full text never quotes, A falsifier written and scored inside Q118 last cycle, cashed again in the second cell line one cycle later: H3K79me2 at the MLL1-N held bins is 0.7008 in RS4;11 (does not fire, threshold 0.75) and 0.9980 in MOLM13 (FIRES) - the same pre-registered clause, opposite verdicts, and nothing in the clause names a cell line, A within-sample share cancels an unknown scale factor but it does NOT make two studies comparable - the same eviction reads as 0.20 over a genome-wide denominator and 0.67 over a promoter-only one, in the same cells on the same day, An MLL1 N-terminus ChIP sees the fusion and wild-type MLL1 in one track, and a menin ChIP has the same problem from the other side - so the standard reagents of the menin-inhibitor literature cannot attribute occupancy to the fusion, and the masking factor is now measured at 3.5 to 4.0-fold, ARID1B (BAF250b) - the cBAF paralogue whose deletion PROMOTES MLL-AF9 leukaemogenesis, which makes it the one gene in this beat whose published KMT2A-fusion result points the wrong way for a drug target, At the 692 RS4;11 bins where an MLL1 N-terminus and menin co-occupy, VTP-50469 takes menin to 0.20 and DOT1L to 0.20, drops H3K79me2 to 0.66, and leaves MLL1-N-reactive material at 0.83 - four factors, one drug, one chromatin, and a clean ordering, At the MLL1-N HELD SET, floor-normalised, the MLL1-N channel is inert to three decimals in both human lines (1.036 and 1.0359) - AND THAT IS A STATEMENT ABOUT THAT POPULATION, NOT ABOUT THE CHANNEL: at MLL1's own top sites in mouse the same channel reads 0.3012 under a DOT1L inhibitor and 0.3298 under a menin inhibitor, At the same bins in the same cells, menin's share ratio is 0.20-0.26 and the MLL1 N-terminus antibody's is 0.80-0.91 - so a shared-epitope MLL1-N ChIP under-reports the menin inhibitor's occupancy effect by 3.5 to 4.0-fold, and the number is now measured rather than asserted, BAHCC1 - a BAH-domain H3K27me3 reader that an MLL fusion binds and upregulates in mouse, and the locus carrying the two largest MLL1-N-reactive rises under a menin inhibitor in human RS4;11, Before quoting anything, this beat re-derived six figures that two earlier beats had stored - three human, three mouse - from the deposited files end to end, and all six came back identical, which is the control that licenses every cross-beat comparison in the entry above it, Both datasets this beat used carry an exposure mismatch that could have produced its results, and both were measured rather than argued away: MOLM13's MENIN pair is 4 days against everything else's 3, and GSE260742's VTP arms are 48 h against 72 h DMSO controls - the first moves a criterion by 0.024 and the second is matched between the two arms being compared, Download and bin GSE127507's nine RS4;11 tracks (1.99 GB), rebuild a human binner, and score the eviction gradient in the index fusion KMT2A::AFF1 - the one measurement that would move this finding from KMT2A::MLLT3 to the disease this graph is about, Fifty-three 2 kb bins gain MLL1-N-reactive signal under VTP-50469 in RS4;11, and the same 53 coordinates gain 1.77-fold in MOLM13 against a class-matched null of 1.01 with the MOLM13 input flat at 1.01 - so there IS a small, reproducible, input-controlled redistribution, and it carries no CpG-island signature, FOXP1 - the forkhead repressor that licenses the pro-B to pre-B transition and blocks apoptosis with NF-kB, sitting at a 105x MLL1-N bin in a leukaemia whose defining lesion is a pro-B arrest, GSE127507 deposits a matched input for BOTH conditions in MOLM13 only - RS4;11 and ML-2 have a DMSO input and no VTP-50469 input - so no input-corrected cross-condition occupancy statement is possible in the human index-fusion line from this series, and none exists anywhere, GSE127507 ran a Drosophila spike-in, measured it, and deliberately did not use it - so the VTP-50469 founding dataset carries no recoverable scale factor either, and the depositors say so in the sample record, Hypothesis: H3K79me2 at a KMT2A fusion's own sites survives menin inhibition when the C-terminal partner contacts DOT1L directly (MLLT3/AF9) and decays when it does not (AFF1) - so the mark's response is a property of the partner and not of menin, which predicts the opposite of the direct-contact intuition and is testable in one line, In human RS4;11 (KMT2A::AFF1), menin occupancy at its own top 0.1% of 2 kb bins falls 14.9x to 2.0x over the track median and its share of total coverage falls to 0.200 - reproducing Q117's murine FLAG-MLLAF9 figures (15.9x to 3.0x, ratio 0.179) to within 1.3-fold on all five statistics, In MOLM13 a menin inhibitor removes three quarters of DOT1L from the fusion's own sites and leaves H3K79me2 there completely intact for three days - the writer and its mark are separable on this timescale, and in RS4;11 they are not, In the human index fusion the menin inhibitor subtracts MENIN and leaves MLL1-N-reactive material in place at the same sites - so the drug's chromatin action is decoupling rather than eviction, and what this literature calls fusion eviction is a menin measurement, Instrument check: the top thirty RS4;11 MLL1-N 2 kb bins recovered from a deposited .tdf are JMJD1C (259x the genome median), ZMYND11, BAHCC1, CDK6, MYB, RUNX2, IGF2BP2, FOXP1, SATB1 and ARID1B - canonical KMT2A::AFF1 targets, annotated only against the series' own RefGene windows, MOLM13 (KMT2A::MLLT3) is the only line in GSE127507 with a matched input in BOTH conditions, and it gives the one differential-input-controlled measurement in the series - MLL1-N occupancy at its own top 0.1% of bins is unchanged (share ratio 0.9438, input 0.9542, input-corrected 0.9891) with ZERO gained bins genome-wide, while menin retains only 13.0% of its own top windows, RS4;11 - the human KMT2A::AFF1 index-fusion line - has a deposited H3K79me2 pair, a MENIN pair, an MLL1-N pair, a DOT1L pair and an input under the same menin inhibitor in GSE127507. Every track needed to run this beat's test on the index fusion exists. The download is 1.99 GB measured by HEAD request, and nobody has run it., RUNX2 - a direct KMT2A-chimera target and dependency in T-ALL, a patient-specific enhancer target in KMT2A::AFF1 B-ALL, and the gene a menin inhibitor represses to restore steroid sensitivity in t(4;11) infants, SATB1 - a nuclear-matrix and PML-body genome organiser with its own matrix-targeting sequence, the clearest subnuclear-localization entry in this beat, and a T-lineage factor that B cells do not need, Stratifying the MOLM13 co-occupied bins by signal amplitude qualifies this beat's own headline: at the strongest tenth the MLL1-N channel falls to 0.5304 and H3K79me2 to 0.7614, so 'MLL1-N does not move' and 'the mark does not move' are both properties of the aggregate - while the ordinal swap that refuted the four-way ordering survives in every stratum, Tag the endogenous KMT2A::AFF1 allele in RS4;11 and ChIP the tag with and without VTP-50469 alongside MENIN and MLL1-N in the same chromatin - the one experiment that converts every occupancy claim in this literature from a reagent statement into a fusion statement, The chromatin compartment that the field treats as 'the fusion's sites' is smaller and less shared in MOLM13 than in RS4;11: 467 of 1,389 MLL1-N-top bins also carry top menin (33.6%) against 692 of 1,390 (49.8%), and the MLL1-N and H3K79me2 compartments barely overlap in either line, The convenient deposited promoter table finds 3 gained windows where the genome-wide re-binning finds 53, because 83% of the gained set is not at a RefGene TSS - so the processed file that makes this dataset cheap to re-use is structurally blind to the answer, The epitope that the whole shared-epitope argument turns on is not documented anywhere this beat could reach: three vendor routes for Bethyl A300-086A returned HTTP 404, so 'MLL1 N-terminus, retained in the fusion' rests on the depositors' own target label and on general fusion architecture, not on an immunogen range, The four-way ordering given a second cell line: menin, DOT1L and the MLL1-N channel reproduce between KMT2A::AFF1 and KMT2A::MLLT3 to within 0.04 of a share ratio, and H3K79me2 - the one channel the ordering was built around - diverges by 0.21 to 0.30 and changes places with MLL1-N, The genome build of GSE127507 is hg19, verified from the chromosome extents written inside each of the nine downloaded .tdf files - 9 bp from hg19 and 2,818,723 bp from hg38 on chr1, in every file - and independently from the deposited TSS table's own coordinates, The measurement that would separate a fusion-partner effect from a lineage effect does not exist: GSE127507 deposits H3K79me2 for RS4;11 and MOLM13 and for ML-2 it deposits DOT1L, MENIN, MLL1n and an input and no H3K79me2 at all, The one experiment that separates fusion partner from lineage: an H3K79me2 ChIP under a menin inhibitor in ML-2 or any KMT2A::AFDN line, alongside the MLL1n and MENIN samples that already exist for that line and can be re-binned for free, Two instruments on the same cell line give opposite answers about DOT1L under a menin inhibitor: the depositors' own TSS-window table puts DOT1L at 0.6638 beside menin's 0.2513, and 2 kb genome-wide bins put it at 0.2219 beside menin's 0.1657 - and only the genome-wide instrument can see the 86% of the co-occupied set that is not at a TSS, Under VTP-50469 in RS4;11, the 209 bins that rise to the top of the MENIN distribution are 3.7-fold CpG-island-enriched over a class-matched null at p = 5.2e-07, while the MLL1-N gained set is not enriched at all - so menin's residue is island-biased and an MLL1-N gain is not, ZMYND11 (BS69) - an H3.3K36me3 reader that restrains elongation, is itself the 5' partner of a chromatin-hijacking AML fusion driving HOXA/MEIS1/MYB, and whose promoter is the third-strongest MLL1-N bin in RS4;11
523. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31497350
     Disruption of the menin-MLL interaction triggers menin protein degradation via ubiquitin-proteasome pathway.

     Wu Y, Doepner M, Hojnacki T, et al. · Am J Cancer Res 2019
     used by A chromatin-occupancy readout has one dimension and the question has three: eviction, degradation and relocation all lower the signal at a target gene, Analysis: separate loss-of-protein from loss-of-occupancy by comparing degron-depletion and menin-inhibition transcriptional time courses, Experiment: spike-in-calibrated, fusion-attributable occupancy of KMT2A::AFF1 in the first 24 hours of menin inhibition, scored for gains as well as losses, Hypothesis: menin inhibition does not merely displace KMT2A::AFF1 from chromatin, it destabilises it — the evicted fusion is degraded, not parked, Risk: the class's pharmacodynamic logic measures menin and reports it as the fusion, in a drug class dosed in infants, Where does the fusion go when menin inhibition evicts it? Almost nobody has looked - the published readouts are chromatin occupancy, the one protein whose fate was measured properly is menin, and the single human observation of fusion loss is confounded by a lineage switch
524. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31821784
     A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia.

     Krivtsov AV, Evans K, Gadrey JY, et al. · Cancer Cell 2019
     used by A chromatin-occupancy readout has one dimension and the question has three: eviction, degradation and relocation all lower the signal at a target gene, A menin inhibitor is not a fusion degron, so watching menin leave chromatin under one cannot identify what was holding it there - every model predicts the same result, A published MLL leukaemia stem-cell programme immortalises progenitors WITHOUT Hoxa or Meis - Myb, Hmgb3 and Cbx5 - and nobody has ever asked what a menin inhibitor does to it, although this graph reads the drug's effect almost entirely through HOXA9 and MEIS1, An occupancy readout returned background in every channel of the only drug-exposed patient sample it has been tried in - so a negative from such an assay cannot currently be told apart from an assay failure, Analysis: separate loss-of-protein from loss-of-occupancy by comparing degron-depletion and menin-inhibition transcriptional time courses, ASNS - the resistance gene for a backbone drug, never measured in this disease, Bounded absence: every chromatin measurement under a menin inhibitor is in an adult-derived line, and none is in an infant KMT2A::AFF1 model, Bounded absence: no published study has tested whether a KMT2A fusion GAINS chromatin sites under a menin inhibitor - and the same pipelines found gains for two other proteins when they looked, Census of every published chromatin-occupancy measurement made under a menin inhibitor: eight datasets, every one TSS-anchored, every one tabulating losses only, Collaborate or compete: an honest matrix, including where the lab would be duplicating a better-resourced effort, Eviction is a claim about menin. The field, and this graph, transfer it to the fusion without a measurement that supports the transfer, Experiment (proposed) — cross-family interface point-mutant panel: is the obligate interface real in each fusion?, Experiment: a 6 / 24 / 72 hour / 7 day VTP-50469 time course in SEM reading menin occupancy and H3K4me3 together, to decide whether the 23% is a partial effect or a slow one, Experiment: five-fraction subcellular blot of a t(4;11) line, with a menin-inhibitor arm - converting thirty years of unattributable images into attributable numbers using only existing antibodies, Experiment: put the resistant and the sensitive fusion side by side - if a MEN1 interface mutant keeps the fusion in place while the wild type moves it, relocation is real and menin is what chooses the address, Experiment: spike-in-calibrated, fusion-attributable occupancy of KMT2A::AFF1 in the first 24 hours of menin inhibition, scored for gains as well as losses, Experiment: spike-in-normalised H3K4me3, menin and IgG CUT&Tag in SEM under VTP-50469 and EPZ-5676 - the one missing experiment that turns every ratio in this beat into an absolute number, First deposit to put both drug classes on the MEN1 channel in one experiment: VTP-50469 leaves ZERO of the 19 DMSO menin peaks at 15 canonical menin-MLL target loci, while EPZ5676 keeps 14, compound 10 keeps 14 and compound 11 keeps 8 - strength-matched permutation p = 0.0003, and the zero is unchanged at every flank from 0 to 100 kb, Forty-one SEM libraries in GSE159608 sort themselves by antibody from the signal alone, across two protocols, two operators and ten months - so the deposit's own labels are confirmed by an instrument that does not share the labels' failure mode, HB11;19 (CVCL_8227) keeps the YEATS domain and expresses both derivative transcripts - so it is the reciprocal-POSITIVE t(11;19) line, and there is no negative one, Hypothesis: menin inhibition does not clear the fusion from chromatin but redistributes it onto the four fifths of the unmethylated CpG address it normally ignores, Hypothesis: menin-inhibitor sensitivity falls with cell-cycle exit, so the compartment that causes relapse is the one the drug reaches least — and nobody has sorted by cycle state to check, Hypothesis: the menin inhibitor's effect is inactivation in place, not eviction - the fusion keeps most of its sites and loses its output, Hypothesis: the three quarters of H3K4me3 that survive menin displacement at fusion target sites are held by a menin-independent complex, and identifying it names the combination partner for a menin inhibitor, In human MOLM13, DOT1L's own occupancy under a menin inhibitor runs 0.1364 / 0.3083 / 0.3555 / 0.3913 across MLL1-N eviction-depth quartiles at Spearman -1.000 - the writer is lost in proportion to eviction depth, and its mark follows with a 2.9-fold smaller span, In MOLM13, human KMT2A::MLLT3, from the VTP-50469 founding paper's own series GSE127507, H3K79me2's aggregate response at MLL1-N's top sites is 0.998 - and the same sites split by eviction depth run 0.7746 / 1.0601 / 1.0995 / 1.1421 at Spearman -1.000, with the INPUT stratified identically staying flat, In murine MLL-AF9, H3K79me2's response to a menin inhibitor runs 0.586 / 0.819 / 0.928 / 1.187 across the four eviction-depth quartiles of the fusion's own top-0.1% sites - Spearman -1.000, span 0.6005, the largest of any mark measured in these bins except H3K27me3 - while the aggregate over the same 1,228 bins is a single unremarkable 0.8156, In SEM, H3K4me3 responds to menin displacement the way a partially redundant mark should: selectively at menin-bound sites, by about a quarter, and not at all under a DOT1L inhibitor - which bounds how much of a menin inhibitor's lethality H3K4me3 can be carrying, In SEM, the infant-derived KMT2A::AFF1 line, VTP-50469 lowers H3K4me3 at menin-bound sites by 23% relative to H3K4me3-matched menin-free sites (95% CI 13-33%), while the DOT1L inhibitor EPZ-5676 changes it by 1% (CI -4 to +6%), Kerry 2017's 'sufficient but not necessary' is a figure title with no experiment behind the second half - and the paper's own knockdowns run the other way, Mechanism class 1 — chromatin and elongation hijack (KMT2A-r, NUP98-r), Menin dependence of KMT2A::MLLT1: real, repeatedly demonstrated, and always as one lane of a partner panel, One demethylase family sits at both ends of this disease - KDM3B gates whether KMT2A rearranges, JMJD1C is what the resulting fusion needs to survive - and a single compound hits both, so its therapeutic index runs in opposite directions in the two cell populations it reaches, Only a handful of loci lose fusion occupancy under a menin inhibitor, and they are the same few whether menin is drugged or deleted: MEIS1, MEF2C, JMJD1C - not HOXA, not MYB, Resolving cycle 83's threat: the MLL1 channel moves under both drug classes and is therefore not diagnostic, but the MEN1 channel separates them completely - so 'menin displacement' remains a specific readout of menin-interface engagement and the corpus must stop treating the two channels as one, Risk: the class's pharmacodynamic logic measures menin and reports it as the fusion, in a drug class dosed in infants, Scott Armstrong & Andrei Krivtsov (Dana-Farber / Boston Children's) — the group that turned menin dependency into a drug, Sort KMT2A-rearranged blasts by cell-cycle state, then measure menin-inhibitor response — the one-week experiment nobody has run, SUPERSEDED IN PART, CYCLE 56 - the MI-2-2 response is ~9x fusion-selective (that stands), but 'does not touch HOXA or MEIS1' was a fact about a weak compound: VTP-50469 collapses MEIS1 -5.25 log2 in the same line, Tested in an independent deposit with an epitope-tagged fusion: of the pivotal paper's three named losers under a menin inhibitor, MEIS1 and JMJD1C reproduce and MEF2C does not; of its three named retained loci, the HOXA cluster reproduces and MYB does not - and GAPDH, the negative control, loses half its share too, The experiment this beat could not do: an epitope-tagged KMT2A::AFF1 ChIP with a Drosophila spike-in, in a human infant-derived B-lineage line, at three replicates and two menin-inhibitor exposures - the design that would turn a within-sample ranking into an absolute occupancy measurement, The menin inhibitor removes three-quarters of the fusion from its own promoters, replicated in two batches, The pivotal menin-inhibitor paper reports that the drug does NOT globally displace MLL1 or the fusion from chromatin - menin goes, the fusion largely stays, The residual fraction this graph says is absent from the entire literature, measured: FLAG-MLLAF9 enrichment at its own top 1,228 sites falls from 15.9x the genome median to 3.0x under VTP50469 - about 18% residual - and 12.8% of those sites stay in the top 0.1%, The state under menin inhibition — differentiation in AML, rapid death in ALL, and a GMP-like exit in the cells that switch lineage instead, The two VTP-50469 H3K4me3 libraries hold 3.3% and 3.8% of their reads in the DMSO-defined peak set against 8.9% for DMSO and 9.4% for EPZ-5676 - one global fact that explains every raw locus difference in the SEM menin-inhibitor arm, and that cannot be resolved into drug effect or library quality, VTP-50469 - the preclinical menin-KMT2A interface inhibitor that almost every chromatin experiment in this field actually used, and which had no entry of its own in this graph, Where does the fusion go when menin inhibition evicts it? Almost nobody has looked - the published readouts are chromatin occupancy, the one protein whose fate was measured properly is menin, and the single human observation of fusion loss is confounded by a lineage switch
525. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30899083
     Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL-USP2 fusions.

     Meyer C, Lopes BA, Caye-Eude A, Cavé H, Arfeuille C, et al., Marschalek R · Leukemia 2019
     used by A five-year-old with KMT2A::USP2 ALL whose MRD would not clear until blinatumomab, then transplant, then more blinatumomab, A nine-month-old with AML whose fusion was found only after every standard test failed, Catalytic-dead UCH test: does KMT2A::USP2 need its deubiquitinase activity to transform?, Enumeration for the USP2 / MAML2 / second-BCR beat: what was searched, what was counted, what was rejected, GATA2 outlier activation in KMT2A::USP2 B-ALL - the only transcriptional output ever measured for this fusion, KMT2A minor breakpoint cluster region (BCR2): intron 20 - exon 24, KMT2A::USP2 is invisible to karyotype and often to FISH, so these patients are misclassified as fusion-negative, KMT2A::USP2, inv(11)(q23.3q23.3) - the minor-BCR fusion that keeps the PHD fingers, KMT2A::USP8, t(11;15)(q23;q21) - three patients, and the second instance of a deubiquitinase partner, The "second breakpoint cluster region" of KMT2A (Meyer 2019): the founding report of BCR2, not a third cluster, The deferred KMT2A partners: what the counts actually are, what was written, what was rejected, and three numbers the previous enumeration got wrong, The partner's deubiquitinase domain is what lets a PHD-retaining KMT2A fusion survive and transform, USP2 (ubiquitin carboxyl-terminal hydrolase 2) - the ninth commonest KMT2A partner and the only one that is a deubiquitinase, USP8 (UBPY) - the second deubiquitinase KMT2A partner, three patients, same UCH logic
526. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31590682
     Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair.

     Ye J, Zha J, Shi Y, Li Y, Yuan D, Chen Q, Lin F, Fang Z · Clin Epigenetics 2019
     used by A menin degrader removes six surfaces; a pocket inhibitor blocks one and touches a second - and in a child receiving TOP2 poisons that difference is a repair-competence difference nobody has measured, CHEK1 (CHK1) - the node where this graph's chidamide synergy actually lands, and the reason that synergy is an HR-impairment argument, CHEK2 (CHK2) - named in every combination mechanism here and measured on its own in none of them, Chidamide (tucidinostat) - the HDAC inhibitor in both of this graph's menin-inhibitor combination papers, and the only one paired with a menin inhibitor in the lymphoid index disease, Fifth explanation for the Fanconi signal: it runs through menin binding FANCD2, not crosslink repair — tested, refuted, prior 0.07, The menin arm and the CTCF arm are not two stories: menin/SETD2/H3K36me3/LEDGF licenses CtIP short-range resection and CTCF/H3K9me/HP1-gamma licenses BRCA1/BARD1-EXO1/DNA2 long-range resection, which are the two consecutive halves of ONE reaction - so a menin inhibitor and an H3K9-axis inhibitor are acting on the same pathway at different steps
527. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30869817
     Whole transcriptome sequencing reveals a KMT2A-USP2 fusion in infant acute myeloid leukemia.

     Ikeda J, Shiba N, Tsujimoto SI, Yoshida M, Nakabayashi K, Ogata-Kawata H, Okamura K, Takeuchi M, Osumi T, Tomizawa D, Hata K, Kiyokawa N, Ito S, Kato M · Genes, Chromosomes & Cancer 2019
     used by A nine-month-old with AML whose fusion was found only after every standard test failed, KMT2A::USP2 is invisible to karyotype and often to FISH, so these patients are misclassified as fusion-negative, KMT2A::USP2, inv(11)(q23.3q23.3) - the minor-BCR fusion that keeps the PHD fingers
528. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30679323
     Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis.

     Agraz-Doblas A, Bueno C, Bashford-Rogers R, et al. · Haematologica 2019
     used by A tested negative: neither fusion product alters DNA double-strand break repair, An anti-MLL-C antibody in a t(4;11) cell is looking at two proteins at once, Analysis (runnable): build a methylome cell-of-origin score for infant KMT2A-rearranged ALL and test it as a predictor of lineage destination, Analysis: score fetal, myeloid-priming and differentiation-stage signatures across public KMT2A-r datasets, At the DNA level almost every KMT2A-rearranged patient has a reciprocal allele - 94% across partners, and 5% have nothing else, Breakpoint anatomy, and an audit of the prognosis claim, Competing model 2: the reciprocal allele is lost as the leukaemia evolves, and losing it selects for something worse, Competing model 3: reciprocal status is a proxy for where the break fell, and the thing that changed is the DIRECT product, Fetal CD19+CD34+CD10-negative PreProB progenitor — a cell that exists before birth and almost not at all after, Fetal liver haematopoietic stem and progenitor cell — the leading candidate cell of origin for t(4;11) infant ALL, Forty-five percent of t(4;11) patients express a KMT2A fusion transcript that keeps the whole WRAD interface, Half of all KMT2A::MLLT1 patients make no reciprocal product at all - a ready-made control arm of about 240 people, Hypothesis: releasing the KMT2A::AFF1 differentiation block sends cells toward myeloid, not mature B, in a measurable fraction of infant cases, Hypothesis: the reciprocal AFF1::KMT2A product protects only when it is structurally complete, so its prognostic effect is a breakpoint class in disguise, Ig-based MRD fails specifically in the KMT2A-rearranged patients whose IGH repertoire is proximally biased and still recombining, In the only cohort that measured it, HOXA genes are ON in exactly the reciprocal-positive patients and OFF in the rest, Infants whose leukaemia expresses the reciprocal fusion survive far better - 62.4% versus 11.7% event-free at four years, Is reciprocal status or breakpoint position used in MRD design or risk stratification? Once, by necessity, in 16 of 3,401 patients - and nowhere in any risk model, Join the KMT2A breakpoint archive to the Interfant MRD and outcome database, on patient, Kinase/PI3K/RAS pathway activation — the only common co-lesion class in KMT2A-r leukemia, and it is mostly subclonal, KMT2A::MLLT1 outcome by age band: favourable in adult ALL, high-risk in childhood AML, and completely unstratified in the infants who are most of the disease, KRAS - the commonest co-mutation in a disease that has almost none, and it is usually in a minority of the cells, KRAS as a co-mutation in KMT2A-r leukemia — the single most frequently co-mutated gene, and it still cannot start the disease, Menin primacy was established on the der(11) product alone and has never been tested against the der(4) product, MRD by Ig/TCR rearrangement: the standard in ALL, and the assay infant KMT2A-rearranged disease strains hardest, NF1 in KMT2A-r leukemia — one homozygous deletion, one missense, and the only loss-of-function co-lesion in the disease, No second driver means no second target - the quiet genome forecloses the combination logic that works in every other leukaemia, NRAS - the other RAS, the one whose 0.3% clone came back, and a UniProt record that lists HRAS1 as its own synonym, NRAS as a co-mutation in KMT2A-r leukemia — the one co-lesion that is specifically enriched in t(4;11), Pentimento and restoration — the fusion overpaints the cell, and cleaning reveals whatever was underneath, Pre-B cell — the stage KMT2A::AFF1 leukaemia never reaches, and why that boundary is informative, PTPN11 in KMT2A-r leukemia — named in every gene list, supported by almost no cases, Reciprocal status is a different fact depending on whether you assay DNA or RNA, and the whole prognostic literature is RNA, Stratify an existing menin-inhibitor cohort by reciprocal fusion status, Subclonal cooperating lesions lost at relapse - what was actually measured, and why 'lost' is the wrong word, The graph's universal 'every KMT2A fusion loses the SET domain' is a silent, propagating error class, The infant breakpoint mutilates the reciprocal protein's first PHD finger - so 'the reciprocal product' is at least two different proteins, The near-silent genome of infant KMT2A-r ALL — 1.3 non-silent mutations, and why that is bad news as well as good, The partner-matched control arm is not 241 versus 219 - it is 153 versus 101, and in that subset the two groups make an identical fusion protein, The pro-B arrest state — what a KMT2A::AFF1 blast is actually doing while it sits there, The quiet genome, audited - the famous 1.3 mutations is a count of point mutations in the dominant clone, and all three of those words do work, The RAS-mutant subclone is where the leukaemia goes, not what it is - a dissemination modifier that a marrow aspirate systematically under-counts
529. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31202577
     Topoisomerase II-Induced Chromosome Breakage and Translocation Is Determined by Chromosome Architecture and Transcriptional Activity.

     Canela A, Maman Y, Huang SN, Wutz G, Tang W, Zagnoli-Vieira G, Callen E, Wong N, Day A, Peters JM, Caldecott KW, Pommier Y, Nussenzweig A · Molecular Cell 2019
     used by Adjudicated: CTCF does not do opposite things at KMT2A - it does one thing, and this graph's contradiction is an untested premise about whether a break becomes a rearrangement, Canela 2019's full text never names MLL or KMT2A, and its HCT116 cohesin arm is lovastatin-arrested in G1 - so the only directional cohesin experiment was run in a cell where transcription-coupled fragility should be lowest, Chromatin loop anchors are DNA-break hotspots - and the two papers that established it disagree about why, CTCF - named in the id of an existing entry in this graph and having no entry of its own, and the protein whose binding sites break preferentially in KMT2A-rearranged patients, CTCF/cohesin occupancy at the KMT2A exon-11 anchor is both the cause of the break and the chaperone of its correct repair - so losing it gives FEWER breaks and MORE rearrangements, Experiment: degrade TOP2A and TOP2B separately in a fetal-like human progenitor and map DNA breaks at the KMT2A locus without a poison, Hypothesis: what breaks KMT2A in a fetus is TOP2B doing its normal transcription-coupled job in a non-cycling progenitor, with no poison involved and repair capacity as the rate-limiting variable, NIPBL - the cohesin loader, the cleanest degron result in the whole architecture literature, and a second bounded absence in this disease, RAD21 - the cohesin subunit with the most break-prone sites in KMT2A-rearranged patients, and the degron experiment this graph keeps asking for, Read from deposited files today: the KMT2A exon-11 CTCF/cohesin element is a top-0.05% etoposide break site on chromosome 11 in a human B-cell-precursor line and in primary CD34+ marrow - and is NOT one in HCT116, the only cell line in which cohesin was ever degraded, SMC3 - the cohesin ATPase arm, the only subunit whose partial loss has been tested directly against a KMT2A fusion, and it was tolerated, TDP2 unglues trapped topoisomerase II from the KMT2A locus - it suppresses translocations overall and manufactures one rare junction class, The cohesin-degron break map was run in the one human cell line where the KMT2A element does not break - so premise (i) is not underpowered, it is unaddressed, The element carries an equally strong CTCF/cohesin peak in HCT116 and in a B-lymphoblastoid line, yet breaks in one and not the other - so occupancy is necessary and not sufficient, and transcription of KMT2A is the switch, The KMT2A exon-11 CTCF/cohesin summit, measured: GRCh38 chr11:118,488,694 (CTCF) and chr11:118,488,677 (RAD21), 17 bp apart, both inside canonical exon 11, The measurement that settles the CTCF dispute: degron-grade CTCF removal versus cohesin removal, with DNA breaks AND rearrangement outcome read out at the same 1 kb of KMT2A in the same cells, reported as rearrangements per break, What the CTCF-protects paper actually cites: it names Gothe and Atkin in ONE direction-free sentence and declares the direction unresolved, and the two papers that ran the reciprocal experiment are absent from all 81 of its references
530. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31202576
     Spatial Chromosome Folding and Active Transcription Drive DNA Fragility and Formation of Oncogenic MLL Translocations.

     Gothe HJ, Bouwman BAM, Gusmao EG, Piccinno R, Petrosino G, Sayols S, Drechsel O, Minneker V, Josipovic N, Mizi A, Nielsen CF, Wagner EM, Takeda S, Sasanuma H, Hudson DF, Kindler T, Baranello L, Papantonis A, Crosetto N, Roukos V · Molecular Cell 2019
     used by Adjudicated: CTCF does not do opposite things at KMT2A - it does one thing, and this graph's contradiction is an untested premise about whether a break becomes a rearrangement, Chromatin loop anchors are DNA-break hotspots - and the two papers that established it disagree about why, Hypothesis: KMT2A and AFF1 break where they do because both breakpoint regions are CTCF/cohesin loop anchors sitting in the same nuclear hub, Read from deposited files today: the KMT2A exon-11 CTCF/cohesin element is a top-0.05% etoposide break site on chromosome 11 in a human B-cell-precursor line and in primary CD34+ marrow - and is NOT one in HCT116, the only cell line in which cohesin was ever degraded, The CTCF site in KMT2A exon 11 - a conserved insulator element sitting exactly on the functional cut point of the breakpoint cluster region, whose occupancy decides whether the locus rearranges, The element carries an equally strong CTCF/cohesin peak in HCT116 and in a B-lymphoblastoid line, yet breaks in one and not the other - so occupancy is necessary and not sufficient, and transcription of KMT2A is the switch, The H3K9me1/2-CTCF brake: a KDM3B-G9a balance keeps the KMT2A breakpoint cluster region methyl-poor and CTCF-bound, and losing either end makes the locus amplify and rearrange - in epithelium, in primary cord-blood progenitors and in mice, TOP2A - the proliferation isoform, the one the drugs are actually measured against, and the only one with a germline association in this disease, TOP2B - the isoform most etoposide-induced KMT2A breaks depend on, resolved genetically and not resolvable pharmacologically, Topoisomerase II cleavage and TOP2 poisons as a source of KMT2A breaks, Why KMT2A picks AFF1: spatial proximity, shared transcription hubs, and the unsettled proximity-versus-damage question
531. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31147444
     Structure of the super-elongation complex subunit AFF4 C-terminal homology domain reveals requirements for AFF homo- and heterodimerization

     Chen Y, Cramer P · J Biol Chem 294:10663-10673 2019
     used by AFF1 / AF4 — domain architecture and residue coordinates, AFF1- and AFF4-containing super elongation complexes occupy physically distinct neighbourhoods in living cells, and KMT2A::AFF1 inherits the AFF1 one, AFF1-AFF4 heterodimerisation through the C-terminal homology domain: the one SEC interface KMT2A::AFF1 certainly keeps, defined by a 2.2 A structure of the wrong subunit, Hypothesis — forced-oligomerisation interfaces are the mutation-resistant drug targets the fusion field has been ignoring, KMT2A::AFF1 oligomerises through the retained AFF1 CHD, putting the commonest fusion in the oligomerisation class, Redesign: the proximity-labelling map of KMT2A::AFF1 cannot be controlled with the wild-type allele - it has to be controlled with time, Separation-of-function test: does KMT2A::AFF1 need its C-terminal homology domain to dimerise?
532. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     PDB 6R80: Structure of AFF4 C-terminal homology domain

     Chen Y, Cramer P · RCSB Protein Data Bank 2019
     used by AFF1-AFF4 heterodimerisation through the C-terminal homology domain: the one SEC interface KMT2A::AFF1 certainly keeps, defined by a 2.2 A structure of the wrong subunit
533. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31413325
     HENA, heterogeneous network-based data set for Alzheimer's disease.

     Sugis E, Dauvillier J, Leontjeva A, Adler P, Hindie V, Moncion T, Collura V, Daudin R, Loe-Mie Y, Herault Y, Lambert JC, Hermjakob H, Pupko T, Rain JC, Xenarios I, Vilo J, Simonneau M, Peterson H · Sci Data 2019
     used by AFF4-FMR1 - DECLINED, and the provenance is the finding: the 'publication' behind this IntAct row is HENA, an Alzheimer's data-integration dataset, not an experiment on AFF4
534. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30635633
     NG2 antigen is a therapeutic target for MLL-rearranged B-cell acute lymphoblastic leukemia.

     · Leukemia 2019
     used by An NG2-directed therapy meets pericytes - and unlike B-cell aplasia there is no replacement therapy for a damaged vascular wall, NG2/CSPG4 is the one antigen in the whole surfaceome that KMT2A::AFF1 itself drives - and it is a pericyte and vascular protein, at 124.5 nTPM in normal blood vessel and 246 TPM in tibial artery, Treat a KMT2A::AFF1 patient-derived xenograft with an NG2-directed agent and read out the CD34+CD19-CD117+ fraction at nadir - does the reservoir the 2006 flow data predicts actually survive?
535. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31283407
     Outcome of Infants Younger Than 1 Year With Acute Lymphoblastic Leukemia Treated With the Interfant-06 Protocol: Results From an International Phase III Randomized Study

     Pieters R, De Lorenzo P, Ancliffe P, et al. · Journal of Clinical Oncology 2019
     used by Analysis (runnable): fit the relapse hazard function in KMT2A-rearranged infant ALL and test whether the cohort is a mixture, Analysis (runnable): value a menin inhibitor as a short-duration instrument — cohort meta-regression plus a discrete-event model of remission months, Anthracycline cardiotoxicity: the heart an infant keeps for sixty years, Breakpoint anatomy, and an audit of the prognosis claim, Buying an already-impaired asset — what diligence would you do, and what is the biological equivalent?, Duration and reinvestment risk — a 4.6-month response is a short-duration instrument, and short duration changes everything about how you value it, Dying in induction: the place where infant protocols actually differ, Experiment: does chemotherapy itself install menin-inhibitor resistance? The two-arm controlled test, plus the serial-sample ladder, Fever and infection: the reason most of these babies see a doctor, and the reason some of them die, Haematopoietic stem cell transplant in KMT2A-rearranged infant leukemia — what it is for, and why most children who need it never get it, How many infants worldwide, not just in the United States, Hyperleukocytosis: why a very high white-cell count is a medical emergency, Hypothesis: KMT2A-rearranged infant ALL is two populations, not one — a mixture-cure model will fit better than proportional hazards, and combination therapy only needs to be given during the first year, Hypothesis: the survival benefit of menin inhibition is governed by the rate at which it delivers patients to a curative consolidation, not by its remission rate — and the field is measuring the wrong thing, Infant acute lymphoblastic leukaemia (ALL diagnosed under 1 year of age), Interfant-06 — 651 infants, and the definitive answer that myeloid-style consolidation does not help, Interfant-99 and Interfant-06: what they report about partners, and what they do not, Is reciprocal status or breakpoint position used in MRD design or risk stratification? Once, by necessity, in 16 of 3,401 patients - and nowhere in any risk model, Join the KMT2A breakpoint archive to the Interfant MRD and outcome database, on patient, KMT2A-rearranged acute lymphoblastic leukaemia, KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23), KMT2A::MLLT1 outcome by age band: favourable in adult ALL, high-risk in childhood AML, and completely unstratified in the infants who are most of the disease, Lymphoid-style versus myeloid-style consolidation — the question asked twice in 1,100 infants, and answered no both times, Mitoxantrone - the Interfant-06 protocol says it is less cardiotoxic than daunorubicin, and the largest survivor cohort ever assembled says it is about seventeen times worse per milligram, Pallor and anaemia in infants: the number this graph quotes does not exist for babies, Ponte-di-Legno non-infant KMT2A-r ALL (n=629): 5-year EFS spans 41.7% to 91.2% across partner-by-lineage cells, Prednisone - the prophase drug, the prognostic factor, and a prodrug that has never itself been tested on a KMT2A-rearranged blast, Rob Pieters, Inge van der Sluis & the Interfant consortium (Princess Maxima Center, Utrecht) — the only global infant-ALL trial network, Step 1: the blood count and the blood film, Term structure of risk — a steeply falling hazard curve is a statement about heterogeneity, not about time, The age confound: a partner arm and an age arm are nearly the same arm, The Interfant-06 backbone, phase by phase: what the protocol every infant reference in this graph points at actually does, The MRD target a centre can run decides which infants are intensified, and the two targets disagree in the direction that matters, The near-silent genome of infant KMT2A-r ALL — 1.3 non-silent mutations, and why that is bad news as well as good, The protocol and era confound: the partner datasets span 1983 to 2016 and outcome moved under them, The white cell count at diagnosis in infants, and why the reported medians disagree by fivefold, WBC 300, age 6 months, MRD 0.01%: three lines drawn by committees, not by biology, WBC 300: a stratification convenience, not a biological threshold - and the evidence says so four different ways, What 160 infants a year actually permits: the sample-size arithmetic, What this beat searched, what it rejected, and the two papers it could not read - after a fifth route rescued the third, When infant leukaemia comes back, it comes back early and while treatment is still running, Where KMT2A-rearranged leukemia physically sits — marrow niche, CNS, blood, liver/spleen and skin
536. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31383639
     Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs

     O'Byrne S, Elliott N, Rice S, Buck G, Fordham N, Garnett C, Godfrey L, Crump NT, Wright G, Inglott S, Hua P, Psaila B, Povinelli B, Knapp DJHF, Agraz-Doblas A, Bueno C, Varela I, Bennett P, Koohy H, Watt SM, Karadimitris A, Mead AJ, Ancliff P, Vyas P, Menendez P, Milne TA, Roberts I, Roy A · Blood 2019
     used by Analysis: score fetal, myeloid-priming and differentiation-stage signatures across public KMT2A-r datasets, Experiment: is the primed state in KMT2A::AFF1 actually bivalent? Multi-mark CUT&Tag on primary infant blasts, Fetal CD19+CD34+CD10-negative PreProB progenitor — a cell that exists before birth and almost not at all after, Fetal liver haematopoietic stem and progenitor cell — the leading candidate cell of origin for t(4;11) infant ALL, Pre-B cell — the stage KMT2A::AFF1 leukaemia never reaches, and why that boundary is informative, Pre-pro-B cell (murine Hardy Fraction A) - the stage before pro-B, with germline immunoglobulin genes, and the stage RYBP loss actually removes, Pro-B cell — the stage at which KMT2A::AFF1 leukaemia is arrested, and the phenotype the diagnosis is made on, The pro-B arrest state — what a KMT2A::AFF1 blast is actually doing while it sits there
537. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30703192
     Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity

     Feijen EAM, Leisenring WM, Stratton KL, Ness KK, van der Pal HJH, van Dalen EC, Armstrong GT, Aune GJ, Green DM, Hudson MM, Loonen J, Oeffinger KC, Robison LL, Yasui Y, Kremer LCM, Chow EJ · JAMA Oncology 2019
     used by Anthracycline cardiotoxicity: the heart an infant keeps for sixty years, Daunorubicin - the anthracycline an infant gets before her first birthday, with a measured null in vitro and sixty years of heart downstream, Doxorubicin - named in twenty entries of this graph, cuts the KMT2A breakpoint where etoposide does, and appears nowhere in Interfant-06, Mitoxantrone - the Interfant-06 protocol says it is less cardiotoxic than daunorubicin, and the largest survivor cohort ever assembled says it is about seventeen times worse per milligram
538. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30865883
     Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity

     Aho ER, Wang J, Gogliotti RD, Howard GC, Phan J, Acharya P, et al. (Tansey WP, senior author) · Cell Reports 26:2916-2928.e13 2019
     used by ASH2L — the WRAD subunit that has DPY30's essentiality profile and none of its co-dependency signal, DPY30 — the smallest COMPASS subunit, and the only one that behaves like a selective dependency, Lost from the KMT2A half: the WIN motif and the whole WRAD interface (aa 3762-3767, Arg3765), RBBP5 — a WRAD subunit that binds the one part of KMT2A every fusion throws away, WDR5 — the partner that is not a partner: it binds the half of KMT2A the fusion throws away, WDR5 and KMT2A are at the centrosome and the midbody - a non-chromatin address for both, with a patient-cell phenotype, WDR5 WIN site and KMT2A Arg3765: measured at 1.7 uM, three co-crystals, and absent from every leukaemic fusion - plus the MLL3 peptide that binds it 51-fold tighter
539. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31164666
     Hematopoietic stem and progenitor cell proliferation and differentiation requires the trithorax protein Ash2l.

     Lüscher-Firzlaff J, Chatain N, Kuo CC, et al. · Sci Rep 2019
     used by ASH2L: the only WRAD subunit ever perturbed in a KMT2A::AFF1 cell, once, weakly
540. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30929739
     De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism.

     Diets IJ; van der Donk R; Baltrunaite K; Waanders E; et al. · Am J Hum Genet 2019
     used by Ask whether the childhood AML in the KDM3B-haploinsufficiency syndrome cohort carried a KMT2A rearrangement - the one human test this mechanism has, and it is a records request, KDM3B - the H3K9me1/2 demethylase that sits on the KMT2A breakpoint cluster region and keeps it from rearranging, and the only leukaemia gene in this graph whose direction of effect flips between the myeloid and the lymphoid literature
541. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31395602
     Targeting PRMT1-mediated FLT3 methylation disrupts maintenance of MLL-rearranged acute lymphoblastic leukemia

     See PubMed record PMID 31395602 for the full author list (not transcribed here) · Blood 2019
     used by Auditing the seven strikes before applying them: nine of ten decisions stand, four for different reasons than were given, and one clinical argument fails, The bite-back of striking a target: a wrong strike costs a cure and generates no data that it was wrong
542. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30902969
     Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis.

     Kelly MJ; So J; Rogers AJ; Gregory G; Li J; Zethoven M; Gearhart MD; Bardwell VJ; Johnstone RW; Vervoort SJ; Kats LM · Nat Commun 2019
     used by BCOR — the other side of the CBX8 conflict, and a target you would be inhibiting in the direction of disease
543. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31697807
     AMP-activated protein kinase links acetyl-CoA homeostasis to BRD4 recruitment in acute myeloid leukemia

     Jiang Y, Hu T, Wang T, et al. · Blood 2019
     used by BET bromodomain inhibition in KMT2A-rearranged leukemia — spectacular preclinically, stalled clinically
544. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31281901
     CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism.

     Piunti A, Smith ER, Morgan MAJ, Ugarenko M, et al. · Sci Adv 2019
     used by Both MBTD1 fusions end at H3K27me3-poor chromatin, one by excluding PRC2 and one by poisoning it - so the shared endpoint is the phenotype and MBTD1 is the coincidence, EPC1 - the NuA4/TIP60 subunit whose C-terminal fragment grips MBTD1, making it the contact a leukaemic fusion cannot do without and the mildest dependency in that whole complex, EZHIP (CXorf67, CATACOMB) - a protein that jams PRC2 by pretending to be an H3K27M oncohistone, and the 3' payload of MBTD1's other fusion, JAZF1 - a 243-residue zinc-finger protein that turned out to be a NuA4 subunit, and the 5' donor of the commonest endometrial-stromal-sarcoma fusion, Low-grade endometrial stromal sarcoma is a family of NuA4-acetyltransferase-to-Polycomb fusions, and that is why one of MBTD1's two fusions looks nothing like the other, MBTD1 is the effector-recruiting half of a leukaemia fusion and the addressing half of a sarcoma fusion while donating nearly all of itself to both - so the junction, not the parts, assigns the role, MBTD1::EZHIP (MBTD1-CXorf67), t(X;17)(p11.2;q21.33) - MBTD1's other fusion, in which a NuA4 subunit delivers an H3K27M-mimicking PRC2 poison to low-grade endometrial stromal sarcoma, One stain, in the right order: H3K27me3 across a low-grade endometrial stromal sarcoma series first, and the three MBTD1::EZHIP blocks second
545. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30923826
     EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma.

     Hubner JM, Muller T, Papageorgiou DN, Mauermann M, et al. · Neuro Oncol 2019
     used by Both MBTD1 fusions end at H3K27me3-poor chromatin, one by excluding PRC2 and one by poisoning it - so the shared endpoint is the phenotype and MBTD1 is the coincidence, EZHIP (CXorf67, CATACOMB) - a protein that jams PRC2 by pretending to be an H3K27M oncohistone, and the 3' payload of MBTD1's other fusion, Low-grade endometrial stromal sarcoma is a family of NuA4-acetyltransferase-to-Polycomb fusions, and that is why one of MBTD1's two fusions looks nothing like the other, MBTD1 is the effector-recruiting half of a leukaemia fusion and the addressing half of a sarcoma fusion while donating nearly all of itself to both - so the junction, not the parts, assigns the role, MBTD1::EZHIP (MBTD1-CXorf67), t(X;17)(p11.2;q21.33) - MBTD1's other fusion, in which a NuA4 subunit delivers an H3K27M-mimicking PRC2 poison to low-grade endometrial stromal sarcoma, The coverage checker the standing brief mandates overwrites its own HGNC index mid-loop, so every symbol after the first no-match is answered wrongly - and the wrong answer is 'treat any answer as unsafe'
546. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31086175
     PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism.

     Jain SU, Do TJ, Lund PJ, Rashoff AQ, et al. · Nat Commun 2019
     used by Both MBTD1 fusions end at H3K27me3-poor chromatin, one by excluding PRC2 and one by poisoning it - so the shared endpoint is the phenotype and MBTD1 is the coincidence, EZHIP (CXorf67, CATACOMB) - a protein that jams PRC2 by pretending to be an H3K27M oncohistone, and the 3' payload of MBTD1's other fusion, MBTD1::EZHIP (MBTD1-CXorf67), t(X;17)(p11.2;q21.33) - MBTD1's other fusion, in which a NuA4 subunit delivers an H3K27M-mimicking PRC2 poison to low-grade endometrial stromal sarcoma, One stain, in the right order: H3K27me3 across a low-grade endometrial stromal sarcoma series first, and the three MBTD1::EZHIP blocks second
547. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     NCBI GEO GSE129524 full sample listing (48 !Sample_title lines) and the GSM3714904 extract protocol quoting both END-seq exonuclease variants, retrieved 2026-09-22

     NCBI Gene Expression Omnibus; submitter Yaakov Maman · NCBI GEO 2019
     used by Break formation, break persistence and break fate are three quantities, and every assay in this dispute reports the middle one - which is why the triad's third premise is ambiguous rather than weak, Canela 2019's RAD21-degron END-seq IS deposited and IS readable today - one sample per arm, no replicates, no minus-auxin control, hg19, bigWig coverage only, Move the cohesin degron into a cell where the element actually breaks: RAD21-AID in Nalm6 or CD34+, sBLISS plus both END-seq variants, with the fusion readout in the same cells
548. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31022428
     Acute myeloid leukemia driven by the CALM-AF10 fusion gene is dependent on BMI1.

     Barbosa K, et al. · Exp Hematol 2019
     used by CALM-AF10 needs BMI1 - and so does MLL-AF9, so this is a shared polycomb dependency and not a point of difference (title corrected 2026-09-21)
549. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31527241
     A higher-order configuration of the heterodimeric DOT1L-AF10 coiled-coil domains potentiates their leukemogenenic activity.

     Song X, et al. · Proc Natl Acad Sci U S A 2019
     used by CALM-AF10 reaches DOT1L through exactly the same OM-LZ interface as KMT2A::MLLT10 - the recruitment transfers, the addressing does not, DOT1L — the target where excellent chemistry met an indirect interaction, Import class 3: the DOT1L-AF10 coiled-coil axis, an MLLT10 mechanism with no counterpart in the index fusion, The DOT1L-AF10 octamer - the second route to H3K79 methylation, required in MLL-AF10 and absent from KMT2A::AFF1
550. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     NCBI GEO GSE99195 full sample listing (18 !Sample_title lines with organism) and GSE129524 GSM records GSM3714899-GSM3714904 (targ=self, view=full, genotype characteristics), retrieved 2026-09-22

     NCBI Gene Expression Omnibus · NCBI GEO 2019
     used by Canela 2017 deposited NO cohesin-depletion experiment - and it did deposit human END-seq in a B-cell-precursor leukaemia line, which nobody here had looked for
551. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     GEO sample records GSM3714939, GSM3714940, GSM3714941 (targ=self, form=text, view=full) compared against the chromosome tables read directly from the deposited bigWig headers with pybigtools 0.3.0 over HTTP range requests, 2026-09-22

     NCBI Gene Expression Omnibus; header read by Q107 · NCBI GEO 2019
     used by Canela 2019's RAD21-degron END-seq IS deposited and IS readable today - one sample per arm, no replicates, no minus-auxin control, hg19, bigWig coverage only
552. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31294507
     Deciphering the Significance of CD56 Expression in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

     Pardo LM, Voigt AP, Alonzo TA, Wilson ER, Gerbing RB, Paine DJ, Dai F, Menssen AJ, Raimondi SC, Hirsch BA, Gamis AS, Meshinchi S, Wells DA, Brodersen LE, Loken MR · Cytometry B Clin Cytom 2019
     used by CBFA2T3::GLIS2, inv(16)(p13.3q24.3)
553. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31031188
     The PAF1c Subunit CDC73 Is Required for Mouse Hematopoietic Stem Cell Maintenance but Displays Leukemia-Specific Gene Regulation.

     Saha N, Ropa J, Chen L, Hu H, Mysliwski M, Friedman A, Maillard I, Muntean AG · Stem Cell Reports 2019
     used by CDC73 / parafibromin — the PAF1C subunit that was genetically tested, and a second tumour suppressor required by the fusion, PAF1c is needed by the normal stem cell and by the leukaemia, and the genes it regulates in each are different
554. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31118806
     T-lymphoid/myeloid mixed phenotype acute leukemia and early T-cell precursor lymphoblastic leukemia similarities with NOTCH1 mutation as a good prognostic factor

     Noronha EP, Marques LVC, Andrade FG, Sardou-Cezar I, Dos Santos-Bueno FV, Zampier CDP, et al., Pombo-de-Oliveira MS · Cancer Management and Research 2019
     used by Cell identities considered and not written: what the search actually returned for basophils, mast cells, eosinophils, NK cells and the rest, Early T-cell precursor (ETP) — the thymocyte that has not yet given up being myeloid, and where KMT2A-rearranged T-ALL sits
555. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31316063
     SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication.

     Halder S, Torrecilla I, Burkhalter MD, Popović M, Fielden J, Vaz B, Oehler J, Pilger D, Lessel D, Wiseman K, Singh AN, Vendrell I, Fischer R, Philipp M, Ramadan K · Nat Commun 2019
     used by CHEK1 (CHK1) - the node where this graph's chidamide synergy actually lands, and the reason that synergy is an HR-impairment argument
556. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31755865
     Chromatin-bound CRM1 recruits SET-Nup214 and NPM1c onto HOX clusters causing aberrant HOX expression in leukemia cells.

     Oka M, Mura S, Otani M, et al. · eLife 2019
     used by Chromatin-bound XPO1 as a shared, druggable address for HOXA-driven leukaemia - and the objection that it may be a general chromatin cofactor rather than an address at all, Docking onto pre-bound XPO1 is a general route to leukaemic chromatin, used by at least seven different lesions - not three coincidences, Experiment: blot menin in a SET-NUP214 immunoprecipitate, then run a menin inhibitor and selinexor alone and combined in LOUCY and MEGAL, How a lift operator became a postal address: the idea behind the XPO1 axis, in plain language, NPM1c and XPO1: one drug, one output, two incompatible mechanisms - is the mutant needed in the cytoplasm or on the chromatin?, NUP214 / CAN - the cytoplasmic-face nucleoporin that CRM1 docks against, and the 3' partner of four leukaemia fusions, SET::NUP214 has no address of its own: chromatin-bound CRM1 is already at HOX, and the fusion's FG repeats dock onto it, The CRM1 address is not a menin-free address: NPM1c reaches HOXA the same way and NPM1c AML is menin-inhibitor-sensitive in the clinic, The entire experimental model space for SET::NUP214 is two cell lines, neither of them in DepMap, with no mouse model found - so every mechanism in this beat is n = 1 or n = 2, The reciprocal ChIP: is chromatin-bound XPO1 present in a KMT2A-rearranged cell, and does a menin inhibitor move it?, Three addresses, one output: what SET::NUP214 actually does to the menin-interface hypothesis, and why it is a weaker test than CALM-AF10, Two pools of one protein: the chromatin-bound XPO1 that matters here has never been separated biochemically from the soluble export machine, Where SET::NUP214 actually is: mobile intranuclear bodies that trap CRM1, dissolve in mitosis and under CRM1 inhibitor, and reassemble on washout, XPO1 / exportin-1 (CRM1) - the cell's main nuclear export receptor, and a chromatin-bound transcriptional scaffold
557. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30573454
     Regulation of MLL/COMPASS stability through its proteolytic cleavage by taspase1 as a possible approach for clinical therapy of leukemia.

     Zhao Z, et al. · Genes Dev 2019
     used by CK2 phosphorylates KMT2A at T2724/S2726 to license taspase1 cleavage - and that site is in the half the fusion throws away, CSNK2A1 (casein kinase 2 alpha) - the one kinase that turns up three separate times in KMT2A biology, Does the fusion 'lose restraint'? The pattern of KMT2A-side loss, and why the tidy reading does not survive contact with the ledger, Experiment: induce CyP33 in a KMT2A-rearranged cell and ask, allele by allele, whether the brake still works at HOXA9, Experiment: titrate wild-type KMT2A up and down in one leukemia cell and watch what happens to the fusion's grip on chromatin, Hypothesis: the fusion is exempt from KMT2A's regulation, not free of it - the brakes still operate at the same loci, on the other allele, Hypothesis: what the KMT2A half loses is control of its own abundance, not control of its activity, Ledger: every module the KMT2A half loses, with coordinates, how each was confirmed, and whether its loss has been shown to matter, Lost from the KMT2A half: both taspase1 cleavage sites (D2666 and D2718) - the fusion is never processed, Lost from the KMT2A half: the FYRN-FYRC clamp (2018-2074 / 3666-3747) that holds wild-type KMT2A together, Lost from the KMT2A half: the transactivation domain (aa 2829-2883) and its CBP contact, S821 is not phosphorylated in any dataset we could query: the 14-3-3 motif candidate is dead as stated, Separating CK2's two routes into KMT2A leukaemia, which every published experiment has confounded, Silmitasertib (CX-4945) - a CKII inhibitor that works on KMT2A-rearranged leukemia by strengthening the allele the fusion does not have, TASP1 (taspase1) - the protease that cuts KMT2A, and the timer the fusion escapes, The anti-MLL-C ambiguity is not a t(4;11) problem - it has three sources, and one KMT2A fusion family is measurably cleaner than the rest, The N320-C180 clamp is the only KMT2A module whose disruption has ever been shown to change subnuclear localisation - and the fusion is the disruption, The protein nobody can attribute by antibody is the one mass spectrometry finds most easily, The second handle on the retained fragment is CK2-dependent, not 14-3-3-dependent
558. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31238957
     Fused in sarcoma silences HIV gene transcription and maintains viral latency through suppressing AFF4 gene activation

     Krasnopolsky S, Marom L, Victor RA, et al. (Taube R, senior author) · Retrovirology 16(1):16 2019
     used by Condensates in KMT2A-fusion leukemia — an honest verdict: not established for AFF1/AFF4/AF9, load-bearing only in ENL-mutant and NUP98 fusions, The case that the KMT2A-fusion condensate is an artefact — what 1,6-hexanediol, overexpressed tags and in-vitro droplets actually prove, Where KMT2A and its fusions sit inside the nucleus — SNL1/SNL2, nuclear speckles and the condensate question
559. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30971819
     Transposon molecular domestication and the evolution of the RAG recombinase

     Zhang Y, Cheng TC, Huang G, Xu A, Xiong Y, Schatz DG, et al. · Nature 2019
     used by Correcting the fusion with genome editing: verdict NOT FEASIBLE for infant leukaemia, though intron-targeted disruption is a real published strategy, Is fusion intended in biology sometimes? Yes, and the answer has a strategic edge, V(D)J recombination: the immune system deliberately cuts its own chromosomes, using a domesticated transposon
560. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31786140
     HOTTIP lncRNA Promotes Hematopoietic Stem Cell Self-Renewal Leading to AML-like Disease in Mice

     Luo H, Zhu G, Xu J, Lai Q, Yan B, Guo Y, Fung TK, Zeisig BB, Cui Y, Zha J, Cogle C, Wang F, Xu B, Yang FC, Li W, So CWE, Qiu Y, Xu M, Huang S · Cancer Cell 2019
     used by CTCF/cohesin boundaries and the HOXA topological domain — the 3D scaffold the fusion program runs on, HOTTIP lncRNA — the 5' HOXA switch that holds the leukemic chromatin domain open
561. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30177838
     A feed-forward loop between nuclear translocation of CXCR4 and HIF-1alpha promotes renal cell carcinoma metastasis

     Bao Y, Wang Z, Liu B, et al. · Oncogene 2019
     used by CXCR4 - named in eighteen entries of this graph with no entry of its own, and the one niche molecule with a drug, a paediatric trial and a direct KMT2A-r experiment
562. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31433977
     Rinf Regulates Pluripotency Network Genes and Tet Enzymes in Embryonic Stem Cells.

     Ravichandran M, Lei R, et al. · Cell Rep 2019
     used by CXXC5 (RINF) - the one CXXC reader measurably down-regulated in KMT2A-rearranged AML, which is the only direction-of-change any family member has in this disease
563. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30679330
     Romidepsin enhances the efficacy of cytarabine in vivo, revealing histone deacetylase inhibition as a promising therapeutic strategy for KMT2A-rearranged infant acute lymphoblastic leukemia.

     Cheung LC, Cruickshank MN, Hughes AM, Singh S, Chua GA, Ford J, et al. · Haematologica 2019
     used by Cyclophosphamide - where the KMT2A literature reports two different activated oxazaphosphorines and only one of them is this drug's metabolite, Cytarabine - the one conventional drug KMT2A-rearranged infant ALL is MORE sensitive to, and the only case in this beat where a mechanism changed a protocol, Daunorubicin - the anthracycline an infant gets before her first birthday, with a measured null in vitro and sixty years of heart downstream, Dexamethasone - the steroid an infant is actually on for most of the protocol, and the one with a high-certainty neurodevelopmental signal in babies, Methotrexate - 5 g/m2 through kidneys that are still maturing, and the one backbone drug the canonical infant sensitivity study never tested, Native E. coli asparaginase - the second-largest in-vitro resistance signal in infant ALL, and a different product from the pegylated one four doses later, Romidepsin - the HDAC inhibitor with the best preclinical case in KMT2A-rearranged INFANT ALL specifically, and a mechanism that is not about histones at all, Vincristine - measured to be no different in KMT2A-rearranged disease, and measured to be UNDERDOSED in infants by the very rule meant to protect them
564. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31588046
     The RNA Helicase DDX6 Controls Cellular Plasticity by Modulating P-Body Homeostasis.

     Di Stefano B, Luo EC, Haggerty C, Aigner S, Charlton J, Brumbaugh J, Ji F, Rabano Jiménez I, Clowers KJ, Huebner AJ, Clement K, Lipchina I, de Kort MAC, Anselmo A, Pulice J, Gerli MFM, Gu H, Gygi SP, Sadreyev RI, Meissner A, Yeo GW, Hochedlinger K · Cell Stem Cell 2019
     used by DDX6 - the only protein ever proposed to do for a cell what Tat does for the virus, on the strength of one 2016 paper
565. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30472189
     Nucleosome Turnover Regulates Histone Methylation Patterns over the Genome.

     Chory EJ, Calarco JP, Hathaway NA, et al. · Molecular Cell 2019
     used by Does KMT2A::AFF1 change histone turnover at its target genes, or does it read a chromatin state it did not make?, Measure all three H3K79 states on a real scale, across a dose series and after a menin inhibitor - the measurement this whole field has been doing by proxy, Measure the clearance clock directly: SNAP-tag H3.3 pulse-chase at KMT2A::AFF1 target genes, with and without DOT1L inhibition, in cycling and arrested cells, The clearance clock has machinery, and the machinery says the clock does NOT stop in a non-dividing cell - a postmitotic heart replaces its histones with a half-life of about two weeks, With no eraser, how fast the histone itself is replaced decides how much H3K79 methylation there is - and that sets the clock a DOT1L drug has to beat
566. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30923167
     Structural basis of recognition and destabilization of the histone H2B ubiquitinated nucleosome by the DOT1L histone H3 Lys79 methyltransferase.

     Jang S, Kang C, Yang HS, Song JJ · Genes Dev 2019
     used by DOT1L does things that have nothing to do with methylation - which is why blocking its active site was never going to remove all of it
567. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     PLoS Genetics S1 Table: identification of PAX5 proximity interactors (PXIs) in pre-B cells, retrieved via Europe PMC supplementaryFiles

     · EMBL-EBI / PLoS Genetics 2019
     used by DOT1L sits in a B-lineage proximity map, and we nearly did not look
568. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31485071
     Structural basis of nucleosome recognition and modification by MLL methyltransferases.

     Xue H, Yao T, Cao M, Zhu G, Li Y, Yuan G, Chen Y, Lei M, Huang J · Nature 2019
     used by DPY30 — the smallest COMPASS subunit, and the only one that behaves like a selective dependency, DPY30 aims the H3K4 machinery while ASH2L powers it, which is why only DPY30 tracks menin, H3K4me3 - the mark KMT2A's own SET domain writes, that the fusion cannot write, that an interface in this graph already binds, and that switches PRC2 off, RBBP5 — a WRAD subunit that binds the one part of KMT2A every fusion throws away, RBBP5: the thinnest fusion literature of the four subunits, and one chromatin datum, Two thirds of the curated interactome of this project's six core proteins is spoke-expanded - and the pairs this graph chose to write are significantly better than the ones it did not, WDR5 and RBBP5: the second arm of the WRAD hub, RBBP5 V375-D376-V377 into the same propeller face, co-crystallised with the MLL1 WIN peptide in one structure
569. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31251903
     Specific inhibition of DPY30 activity by ASH2L-derived peptides suppresses blood cancer cell growth.

     Shah KK, Whitaker RH, Busby T, et al. · Exp Cell Res 2019
     used by DPY30: the founding negative does not cover it, and it has no KMT2A contact to lose
570. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31399344
     The Histone Deacetylase SIRT6 Restrains Transcription Elongation via Promoter-Proximal Pausing.

     Etchegaray JP, Zhong L, Li C, et al. · Mol Cell 2019
     used by ELL2 — a SEC subunit that almost no cell needs, next to a paralogue almost every cell needs
571. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31341009
     ELP3 Acetyltransferase is phosphorylated and regulated by the oncogenic anaplastic lymphoma kinase (ALK).

     Li MT, Liang JY, et al. · Biochem J 2019
     used by ELP2 (STATIP1/StIP1) - the double beta-propeller of the Elongator core, whose informal name collides with a different human gene and whose STAT3 function is a by-similarity annotation, ELP3 - the catalytic subunit, the only Elongator protein with a real acetyltransferase domain, and the one whose loss in mouse blood causes marrow failure and then p53-mutant leukaemia
572. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31243293
     DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation

     Godfrey L, Crump NT, Thorne R, et al. (Milne TA, senior author) · Nature Communications 10(1):2803 2019
     used by Enhancer usage in KMT2A-rearranged leukemia — occupancy and amplification, not hijacking, and not super-enhancers, Enhancer-promoter contacts at KMT2A-fusion target loci — what the fusion uses, what it does not, and what survives the drug, H3K27ac - named in 40 entries with no entry of its own, and the strongest KMT2A::AFF1 measurement of it is invisible to every abstract search, H3K79me2 - the di-methyl state the leukaemia actually runs on, and the one menin turns out to govern only half of, H3K9me3 - measured in KMT2A::AFF1 cells, in a supplementary figure, and it rises GENERALLY where H3K27ac falls SPECIFICALLY in the same experiment, Step 4 — The histone mark: DOT1L and H3K79me2/3 at fusion target genes (and why global expression barely moves), The imports that were never necessary: H3K79 methylation in KMT2A::AFF1 has its own literature, and this graph barely cites it, The noncoding dependency screen five hypotheses in this graph are waiting on - and the KMT2A-rearranged screen that already exists and bounds it
573. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31234226
     ZNF384-fusion proteins have high affinity for the transcriptional coactivator EP300 and aberrant transcriptional activities.

     Yamamoto H, Hayakawa F, Yasuda T, Odaira K, Minamikawa Y, Tange N, Hirano D, Kojima Y, Morishita T, Tsuzuki S, Naoe T, Kiyoi H · FEBS Lett 2019
     used by EP300::ZNF384 - the commonest ZNF384 fusion, and it throws away the acetyltransferase, How common is ZNF384-rearranged leukaemia? Published answers span 1.6% to about 20% and the spread is almost entirely denominator, not biology, The necessary lesion in ZNF384-rearranged leukaemia is LOSS of the ZNF384 C-terminus, not GAIN of a fusion partner
574. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     GSE139196: SUV39H1 (KMT1A) and H3K9me3 ChIP-seq in MCF-7 with and without estradiol - GSM4133857-60, GSM4585206-207, HOMER bedGraph on hg38

     Yang F, et al. · NCBI GEO 2019
     used by Estradiol does not redistribute SUV39H1 - because the replicates do not agree well enough to see it: over 56,171 CTCF anchors the ACROSS-condition Spearman (0.358) is HIGHER than the within-condition replicate correlations (0.326 for -E2, 0.207 for +E2), and the same 147 bp anchor reads 51.8, 69.1, 90.8 and 96.3 in the four samples, In MCF-7 the two signals point in opposite directions over the same 90 kb: H3K9me3 sits at the 15.8th and 10.3rd percentile of 56,171 same-cell CTCF anchors across the KMT2A gene body (0.82x and 0.65x the random-tile mean) while SUV39H1 sits at the 81.7th-86.8th in all four of its tracks - and the 147 bp anchor carries ZERO H3K9me3 in the minus-estradiol track, Measured genome-wide, not just at the locus: the median WITHIN-CONDITION replicate disagreement between two ChIP-seq tracks at a 146 bp window is 23.48 percentile points across 56,171 CTCF anchors and 12 replicate pairs, rising to 57-83 points at the 90th percentile of anchors - and the KMT2A exon-11 element sits at the 35.8th percentile of that distribution, so it is NOT unusually noisy, 146 bp windows are, NEITHER, and it is the closest call this project has had: KAP1/TRIM28 reads the 90.62nd, 81.85th and 89.45th percentile of MCF-7 CTCF anchors at the exon-11 element in three of four tracks - satisfying the first clause of the pre-registered PRESENT rule - and the six-non-anchor-interval clause blocks it at 65.87, RUN, with its positive control: knocking down KDM4B and KDM4C together raises H3K9me3 at the +1 nucleosome of 2,000 active promoters by 35.7 percentile points, moves the KMT2A promoter's +1 nucleosome by the same 35.3, and moves the 90 kb KMT2A gene body 5.05 points the WRONG way - so the methyl-poor domain is not an erasure product, RUN: endogenous HP1a/CBX5 is DEPLETED at the exon-11 anchor (median 23.94th percentile) and has the lowest KMT2A gene-body reading of any protein in the panel (30.16) - while the phosphomimetic Bio-ChIP mutant 4E reads higher than the phospho-compromised 4A at all seven intervals AND that difference falls inside the genome-wide interquartile range of the same comparison, so it carries no information, RUN: G9a/EHMT2 reads the 95.8th percentile of 56,171 same-cell-type CTCF anchors at the KMT2A promoter in all four MCF-7 ChIP-seq tracks, and a median 33.42nd at the exon-11 anchor - so the cheapest test of hyp-q114's third prediction REFUTES it, RUN: KDM4B and KDM4C both read the 76.6th-79.7th percentile of MCF-7 CTCF anchors over the whole 90 kb KMT2A gene body - above the 25-track panel median of 61.39, LOCUS-WIDE ELEVATED - and both are ORDINARY at the exon-11 anchor with replicate spreads of 92.3 and 61.5 percentile points, THE DEFLATING NULL, RUN: matching on gene length AND MCF-7 expression roughly HALVES the H3K9me3 depletion over the KMT2A gene body - from the 7.6th-15.0th percentile of class-matched CTCF anchors to the 18.2nd-23.4th of 385 matched transcribed gene bodies - so the methyl-poor breakpoint domain is partly a fact about transcription and does not dissolve into one, The deposit this graph filed as 'four SUV39H1 ChIP-seqs' is actually 77 samples in MCF-7 carrying the ENTIRE H3K9 axis in one cell type and one pipeline - writer SUV39H1, writer G9a/EHMT2, reader HP1-alpha/CBX5 (wild-type AND two phospho-mutants), co-repressor KAP1/TRIM28, erasers KDM4B and KDM4C, the mark H3K9me3, and an shKDM4B+shKDM4C eraser-knockdown arm, The experiment this beat could not do: G9a, HP1a, KAP1 and H3K9me3 at the KMT2A promoter and exon-11 anchor in a KMT2A-rearranged B-lineage cell and a CD34+ progenitor, WITH an input arm, an IgG arm and a same-cell CTCF arm, The H3K9 machinery's address at KMT2A is the PROMOTER, not the exon-11 breakpoint anchor: G9a, HP1a and KAP1 all read the top decile of active promoters there in MCF-7 and KAP1's peak replicates a K562 peak to 267 bp, while five proteins across five cell types are ORDINARY or absent at the anchor - so every H3K9-directed intervention this graph has discussed is aimed 52 kb from where the machinery is, The MCF-7 arm, and the clause that saved it: SUV39H1 at the exon-11 anchor reaches the 96.3rd percentile of 56,171 same-cell-type CTCF anchors in one replicate - but all six non-anchor KMT2A intervals are elevated too (medians 73-87), so the pre-registered FIRES clause does not fire, the verdict is NEITHER, and four replicates of one antibody in one cell line span 51.8 to 96.3 at the same 147 bp, THE POSITIVE RESULT: the writer G9a, the reader HP1a and the scaffold KAP1 all sit on the KMT2A PROMOTER in MCF-7 at the 87.6th-98.9th percentile of 2,000 ACTIVE promoters - surviving the control that says an active promoter is ChIP-hot for everything - while none of the three is above the 75th percentile at the exon-11 anchor 52 kb away
575. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31776511
     MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment.

     Calvanese V, Nguyen AT, et al. · Nature 2019
     used by Expressed, required, maintains — three different claims about where a gene matters, and the graph must label which one it has, MLLT3 runs normal stem-cell self-renewal and is required in essentially no leukaemia line — the inverted case, The transfer rule: which MLL-AF9 results can be carried into t(11;19) and t(4;11), and which are statements about a protein missing a reading module
576. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31451685
     EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells.

     Ragazzini R, Perez-Palacios R, Baymaz IH, Diop S, et al. · Nat Commun 2019
     used by EZHIP (CXorf67, CATACOMB) - a protein that jams PRC2 by pretending to be an H3K27M oncohistone, and the 3' payload of MBTD1's other fusion
577. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 31861091
     Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia.

     Kettyle LM, Lebert-Ghali CÉ, et al. · Cancers (Basel) 2019
     used by FANCG — FA core complex; rank 27 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all, FANCI — ID2 module; rank 15 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
578. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31186273
     NPM1c alters FLT3-D835Y localization and signaling in acute myeloid leukemia.

     Rudorf A, Muller TA, Klingeberg C, Kreutmair S, Poggio T, Gorantla SP, Ruckert T, Schmitt-Graeff A, Gengenbacher A, Paschka P, Baldus C, Zeiser R · Blood 2019
     used by FLT3-ITD signals from inside the cell, not from the surface - and whether it is the ER or the Golgi decides which pathway fires
579. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30626973
     FTSJ3 is an RNA 2'-O-methyltransferase recruited by HIV to avoid innate immune sensing.

     Ringeard M, Marchand V, Decroly E, Motorin Y, Bennasser Y · Nature 2019
     used by FTSJ3 (Q8IY81) - the pre-rRNA 2'-O-methyltransferase at the weakest edge of the MLL-fusion nucleolar block: two baits of seven, not the index fusion, and never screened
580. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31628328
     Phagocytosis is mediated by two-dimensional assemblies of the F-BAR protein GAS7.

     Hanawa-Suetsugu K, Itoh Y, Ab Fatah M, Nishimura T, Takemura K, Takeshita K, et al. · Nat Commun 2019
     used by GAS7 — growth-arrest-specific F-BAR protein, the second pillar of the forced-oligomerisation model, Hypothesis: tubulin/microtubule association is a recurrent, unnamed property of the KMT2A partners whose transforming module has no other assignment
581. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31775874
     Histone methyltransferases EHMT1 and EHMT2 (GLP/G9A) maintain PARP inhibitor resistance in high-grade serous ovarian carcinoma.

     Watson ZL, Yamamoto TM, McMellen A, Kim H, Hughes CJ, Wheeler LJ, et al. · Clinical Epigenetics 2019
     used by Giving a G9a/GLP inhibitor alongside etoposide or doxorubicin removes a DNA-repair licence at the moment TOP2 breaks are being made - and the sibling compound UNC-0638 is measured to block BRCA1/BARD1 arrival at a break, in children on curative therapy, The CTCF licensing cascade: CTCF recruits HP1-gamma, KAP1, SUV39H1, SETDB1 and KDM5A to a break, that repressive chromatin licenses EARLY BRCA1/BARD1, and early BRCA1/BARD1 licenses EXO1/DNA2 long-range resection - measured entirely in U2OS and HEK-293T, with engineered breaks and one etoposide arm
582. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     NCBI GEO SuperSeries GSE121742 and SubSeries GSE121740/GSE121741 - esummary db=gds records, supplementary filelist.txt for GSE121742 and GSE121740 with all 36 file entries and byte sizes, full sample listing with source and organism, and the complete GSM3687237 record

     NCBI Gene Expression Omnibus; submitters Gothe HJ, Bouwman BAM, Crosetto N, Roukos V · NCBI GEO 2019
     used by Gothe 2019's deposit is all-human, has base-resolution break lists, includes primary CD34+ marrow and a transcription-inhibition arm - and contains no CTCF or cohesin perturbation of any kind
583. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30808685
     The impact of the graft-versus-leukemia effect on survival in acute lymphoblastic leukemia.

     Yeshurun M, Weisdorf D, Rowe JM, Tallman MS, Zhang MJ, Wang HL, Saber W, de Lima M, et al. · Blood Advances 2019
     used by Graft-versus-host disease in a transplanted infant - the only antileukaemic benefit and the main cause of death are the same process at different grades, Graft-versus-leukaemia in KMT2A-rearranged infant leukaemia - the mechanism the whole transplant rests on, demonstrated in ALL generally, assumed in this disease, and with a published mechanistic reason to doubt it
584. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31378783
     Asymmetrical methyltransferase PRMT3 regulates human mesenchymal stem cell osteogenesis via miR-3648.

     Min Z, Xiaomeng L, Zheng L, Yangge D, et al. · Cell Death Dis 2019
     used by H4R3me2a - the activating arginine mark that a KMT2-family enzyme's OWN tandem PHD module reads, where the Kabuki-syndrome mutations sit, and which no KMT2A-fusion study has ever measured, PRMT3 - the mostly-cytoplasmic ribosome methyltransferase that also writes the ACTIVATING mark on the residue PRMT5 represses, has an acute-leukaemia degrader, and is invisible to this project's own mark-query rule
585. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31501518
     Tracing the first hematopoietic stem cell generation in human embryo by single-cell RNA sequencing

     Zeng Y, He J, Bai Z, Li Z, Gong Y, Liu C, Ni Y, Du J, Ma C, Bian L, Lan Y, Liu B · Cell Research 2019
     used by Haemogenic endothelium — the vessel-wall cell that gives birth to blood
586. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30679325
     Enhanced hemato-endothelial specification during human embryonic differentiation through developmental cooperation between MLL-AF4 and AF4-MLL fusions

     Bueno C, Calero-Nieto FJ, Wang X, Valdés-Mas R, Gutiérrez-Agüera F, Roca-Ho H, Ayllon V, Real PJ, Arambilet D, Espinosa L, Torres-Ruiz R, Agraz-Doblas A, Varela I, de Boer J, Bigas A, Gottgens B, Marschalek R, Menendez P · Haematologica 2019
     used by Haemogenic endothelium — the vessel-wall cell that gives birth to blood, Is KMT2A::AFF1 leukemia epithelial or endothelial? No — it is haematopoietic. But the question is a good one, Put both fusion proteins in the same cell and you get something neither produces alone
587. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31049581
     HCF-2 inhibits cell proliferation and activates differentiation-gene expression programs.

     Gudkova D, Dergai O, Praz V, Herr W · Nucleic Acids Res 2019
     used by HCFC2 — menin's other host cell factor, present in the founding paper by gel filtration and never mentioned again
588. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31590891
     HEXIM1 Diffusion in the Nucleus Is Regulated by Its Interactions with Both 7SK and P-TEFb.

     Furlan A, et al. · Biophys J 2019;117:1615-1625 2019
     used by HEXIM1 - the brake pad, the only part of the reservoir anyone has deliberately raised in a KMT2A-rearranged cell, and the result was that the leukaemia grew less
589. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31805991
     Inhibition of the histone demethylase, KDM5B, directly induces re-expression of tumor suppressor protein HEXIM1 in cancer cells.

     Montano MM, Yeh IJ, Chen Y, et al. · Breast Cancer Res 2019
     used by HEXIM1 - the brake pad, the only part of the reservoir anyone has deliberately raised in a KMT2A-rearranged cell, and the result was that the leukaemia grew less
590. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30952900
     The human HOXA9 protein uses paralog-specific residues of the homeodomain to interact with TALE-class cofactors

     Dard A, Jia Y, Reboulet J, Bleicher F, Lavau C, Merabet S · Scientific Reports 9:5664 2019
     used by How HOXA9 binds DNA: a hexapeptide into a PBX pocket, a 1.9 A structure that is mouse HoxA9 plus human Pbx1 homeodomains, and a second route that makes the motif redundant, The druggable node in the homeodomain code is the MEIS1-PBX3 interface, not the HOX-PBX one - and it is the only one nobody has attacked, The HOX-PBX interface, and its one peptide: HXR9/HTL001 has been tried in eight tumour types and in KMT2A-rearranged leukaemia exactly once, The PBX3-MEIS1 dimer, not HOXA9, is the unit that reproduces the MLL-fusion transcriptome - and it turns the HOXA cluster on from underneath
591. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 30551418
     TCF7L2 activated HOXA-AS2 decreased the glucocorticoid sensitivity in acute lymphoblastic leukemia through regulating HOXA3/EGFR/Ras/Raf/MEK/ERK pathway

     Zhao Q, Zhao S, Li J, Zhang H, Qian C, Wang H, Liu J, Zhao Y · Biomedicine & Pharmacotherapy 109:1640-1649 2019
     used by HOXA-AS2 and HOXA-AS3 — mid-cluster antisense transcripts with essentially no KMT2A-r evidence
592. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31717699
     Perturbation of Methionine/S-adenosylmethionine Metabolism as a Novel Vulnerability in MLL Rearranged Leukemia.

     Barve A, Vega A, Shah PP, et al. · Cells 2019
     used by IGF2BP3 — an RNA-binding protein required for MLL-Af4 leukaemogenesis in mice that CRISPR barely touches in human lines
593. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30730614
     Flow cytometric predictive scoring systems for common fusions ETV6/RUNX1, BCR/ABL1, TCF3/PBX1 and rearrangements of the KMT2A gene, proposed for the initial cytogenetic approach in cases of B-acute lymphoblastic leukemia.

     Tsagarakis NJ, ..., Paterakis G · Int J Lab Hematol 2019
     used by IL3RA / CD123 - not just a myeloid target: the quartile of CD123 expression that carries the KMT2A rearrangements is the quartile that dies, MME / CD10 (CALLA) - the marker this disease is defined by NOT having, and the promoter is methylated shut rather than simply not yet switched on, What an immunophenotype can and cannot tell you about a genotype - the arithmetic of a surrogate marker, worked on NG2
594. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31022259
     Inducible expression of immediate early genes is regulated through dynamic chromatin association by NF45/ILF2 and NF90/NF110/ILF3.

     Wu TH, Shi L, Lowe AW, et al. (5 authors; senior author Kao PN) · PLoS One 2019
     used by ILF3 / NF90 - a nucleolar dsRNA-binding coactivator whose chromatin residency was mapped in the same leukaemia line that proximity-labelled KMT2A
595. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30315824
     Distinct pathways affected by menin versus MLL1/MLL2 in MLL-rearranged acute myeloid leukemia.

     Chen Y, Jones KL, Anastassiadis K, et al. · Exp Hematol 2019
     used by In a cell with no fusion, a menin inhibitor is substantially a KMT2B drug, KMT2B (MLL2/MLL4) - the other protein menin binds, and the one this graph never wrote, KMT2B has no haematopoietic cell-state result, and two of the seven records that look like one are about a different gene in muscle, Measure the menin-KMT2B affinity nobody has measured, and the four clinical inhibitors' IC50 against it, Menin holds KMT2A and KMT2B, and the graph has been written as if it held one, The KMT2-family beat's own ledger: every query run, every gene dropped, every paper read and not used, When a family shares a complex, the result is family-selective, not member-selective - the protein version of this graph's inhibitor-class rule
596. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     ENCODE blacklist v2 for hg19, Boyle-Lab/Blacklist lists/hg19-blacklist.v2.bed.gz - 834 intervals, fetched 2026-09-23

     · Boyle-Lab/Blacklist (GitHub) 2019
     used by In human RS4;11 (KMT2A::AFF1), menin occupancy at its own top 0.1% of 2 kb bins falls 14.9x to 2.0x over the track median and its share of total coverage falls to 0.200 - reproducing Q117's murine FLAG-MLLAF9 figures (15.9x to 3.0x, ratio 0.179) to within 1.3-fold on all five statistics
597. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31208993
     FusionPro, a Versatile Proteogenomic Tool for Identification of Novel Fusion Transcripts and Their Potential Translation Products in Cancer Cells.

     Kim CY, Na K, Park S, et al. · Mol Cell Proteomics 2019
     used by In-silico digest of 81 modelled KMT2A fusion junctions: the peptide that would prove the fusion protein exists, No KMT2A fusion junction peptide has ever been reported - the one measurement that would prove the protein exists has not been published
598. speculative confidence 1 of 5: Our own inference or analogy. Not shown to be true.paperPMID 31138034
     miR-153-3p Suppresses Inhibitor of Growth Protein 2 Expression to Function as Tumor Suppressor in Acute Lymphoblastic Leukemia.

     Jiang J, Liu Y, Zhao Y, Tian F, Wang G · Technology in Cancer Research and Treatment 2019
     used by ING2 - the PHD finger that reads H3K4me3 and turns it into REPRESSION, and whose founding co-crystal is filed under the MOUSE accession
599. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31076406
     Critical role of Jumonji domain of JMJD1C in MLL-rearranged leukemia.

     Izaguirre-Carbonell J; Christiansen L; Burns R; Schmitz J; Li C; Mokry RL; et al. · Blood Adv 2019
     used by JMJD1C / KDM3C - named in three entries of this graph as one of the only loci that loses fusion occupancy under a menin inhibitor, ranked 23rd of 17,728 for KMT2A-selective dependency in this project's own scan, with the strongest published shRNA effect in SEM - and no entry until now
600. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31471323
     KDM2B in polycomb repressive complex 1.1 functions as a tumor suppressor in the initiation of T-cell leukemogenesis.

     Isshiki Y, Nakajima-Takagi Y, Oshima M, Aoyama K, Rizk M, Kurosawa S, Saraya A, Kondo T, Sakaida E, Nakaseko C, Yokote K, Koseki H, Iwama A · Blood Adv 2019
     used by KDM2B — 513 potent ChEMBL rows that are mostly patent bins, and no structure of the domain they claim to inhibit, PCGF1 — the PRC1.1 scaffold whose LOSS causes menin-inhibitor resistance, so it is a restraint on the leukaemia rather than a dependency of it, PRC1.1 — the complex this graph has been leaning on, now enumerated subunit by subunit, and the enumeration changes the conclusion