Bibliography, page 8

1. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 20592248
   Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study

   Mann G, Attarbaschi A, Schrappe M, De Lorenzo P, Peters C, Hann I, De Rossi G, Felice M, et al. · Blood 2010
   used by Who gets transplanted in infant KMT2A-rearranged ALL, and whether it helps - four criteria, and a literature that points both ways
2. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 20048001
   A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP).

   Zhao B, Li L, Tumaneng K, Wang CY, Guan KL · Genes Dev 2010
   used by YAP1 (P46937) - the Hippo pathway's transcriptional co-activator, and a KMT2A fusion partner from a completely different functional class
3. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19528532
   Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study.

   Balgobind BV, Raimondi SC, et al. · Blood 2009
   used by 756 children with 11q23/MLL-rearranged AML: 5-year EFS runs from 11% to 92% depending on the partner, I-BFM childhood KMT2A-r AML (n=1,130): the 3-prime partner defines two risk groups that differ by 24 EFS points, KMT2A-rearranged acute myeloid leukaemia in children and infants, KMT2A::AFDN (MLL-AF6), t(6;11)(q27;q23), KMT2A::ELL (MLL-ELL), t(11;19)(q23;p13.1), KMT2A::MLLT10 (MLL-AF10), t(10;11)(p12;q23), KMT2A::MLLT3 (MLL-AF9), t(9;11)(p21.3;q23.3), KMT2A::MLLT3 across 612 genotyped patients: myeloid at every age, but 248 of them have ALL, and 157 of those are infants, One karyotype band, two partner genes: why t(11;19) and t(10;11) can cancel a real partner effect, Which partner, in which patient: KMT2A partner frequencies across six age-lineage strata
4. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19584866
   A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma.

   Erkizan HV, Kong Y, Merchant M, Schlottmann S, Barber-Rotenberg JS, Yuan L, Abaan OD, Chou TH, Dakshanamurthy S, Brown ML, Uren A, Toretsky JA · Nat Med 2009
   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.
5. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19200802
   Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells.

   Somervaille TC, Matheny CJ, Spencer GJ, Iwasaki M, et al. · Cell Stem Cell 2009
   used by 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, CBX5 / HP1-alpha (P45973, 191 aa) - the H3K9me3 reader that recruits the writer, the writer's destroyer and the second writer; and the one member of that circuit with a published pro-leukaemic role, as part of an MLL leukaemia stem-cell programme that immortalises myeloid progenitors WITHOUT Hoxa or Meis
6. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19430464
   Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger.

   Wang GG, Song J, Wang Z, Dormann HL, Casadio F, Li H, Luo JL, Patel DJ, Allis CD · Nature 2009
   used by 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., NUP98::KDM5A (NUP98-JARID1A), t(11;12)(p15;p13)
7. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19558506
   Two independent gene signatures in pediatric t(4;11) acute lymphoblastic leukemia patients

   Trentin L, Giordan M, Dingermann T, Basso G, Te Kronnie G, Marschalek R · European Journal of Haematology 83(5):406-419 2009
   used by Analysis (runnable): does the infant methylome predict HOXA status once age and breakpoint are controlled?, Do different breaks give different biology? A verdict on partner identity vs breakpoint position, HOXA-high versus HOXA-low KMT2A-rearranged leukemia — the split that breaks the one-mechanism story, Hypothesis: the cell-of-origin methylome, not the breakpoint, decides whether a KMT2A::AFF1 leukemia is HOXA-high or HOXA-low, KMT2A exon 11 / intron 11 breakpoints (BCR subregion C): the infant, HOXA-low, topoisomerase-II-associated break, KMT2A intron 9 / exon 9 breakpoints (BCR subregion A): the HOXA-high, older-patient break, The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential
8. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19855078
   Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options

   Stumpel DJPM, Schneider P, van Roon EHJ, et al. (Stam RW, senior author) · Blood 114(27):5490-5498 2009
   used by Analysis (runnable): does the infant methylome predict HOXA status once age and breakpoint are controlled?, Experiment: is the primed state in KMT2A::AFF1 actually bivalent? Multi-mark CUT&Tag on primary infant blasts, Hypothesis: t(4;11) infant ALL is a hypermethylated genome whose transposable elements can be reawakened, and that reawakening is an untested immunotherapeutic lever, Hypothesis: the cell-of-origin methylome, not the breakpoint, decides whether a KMT2A::AFF1 leukemia is HOXA-high or HOXA-low, microRNA genes silenced by CpG hypermethylation in t(4;11) infant ALL — the non-coding genome the fusion switches OFF, The differentiation block — what it actually is, operationally, in KMT2A::AFF1 leukaemia, The KMT2A-r DNA methylation signature — focal hypermethylation, no global hypomethylation, and a hypomethylating agent that did not help, The primed chromatin state — what is actually established, and why the word 'bivalent' should be used carefully here
9. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19411627
   Discordance of MLL-rearranged (MLL-R) infant acute lymphoblastic leukemia in monozygotic twins with spontaneous clearance of preleukemic clone in unaffected twin

   Chuk MK, McIntyre E, Small D, Brown P · Blood 2009
   used by Are the fusions temporary? No: the KMT2A fusion is the one thing that does not change between diagnosis and relapse, Fusion-positive clones that never become leukaemia: persistence in remission, spontaneous clearance, and silent rearrangements in healthy people, Hypothesis: KMT2A::AFF1 is continuously required, not a hit-and-run initiator whose job is done once the epigenome is set, Latency: months from the fusion forming in a fetus to leukaemia in an infant, against years or a decade for every other backtracked fusion, Newborn screening for leukaemia fusions: verdict NOT FEASIBLE TODAY, and the reason is arithmetic plus the absence of anything to offer a positive, Twin concordance: near-total for infant KMT2A-rearranged leukaemia, about 5% for childhood ALL overall
10. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19234465
    PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing.

    Zhao Q, Rank G, Tan YT, Li H, et al. · Nat Struct Mol Biol 2009
    used by 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, H4R3me2s - the repressive symmetric arginine mark that recruits DNMT3A, blocks a KMT2 enzyme's own PHD module, and is the ONLY arginine mark ever measured in a KMT2A-fusion system
11. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19703992
    Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II.

    Wang P, Lin C, Smith ER, Guo H, Sanderson BW, Wu M, Gogol M, Alexander T, Seidel C, Wiedemann LM, Ge K, Krumlauf R, Shilatifard A · Mol Cell Biol 2009
    used by At the Hox cluster, menin is required for most of the H3K4 methylation and MLL1 is required for only a subset - the cofactor has a bigger chromatin footprint than the enzyme, 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, KMT2A / MLL1 — the gene that breaks, KMT2A is called an H3K4 methyltransferase, and it is required for the mark at under 5% of the promoters that carry it, MEN1 / menin — the adaptor the fusion cannot work without
12. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19109178
    CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4-ATF3-CHOP cascade.

    Mungrue IN, Pagnon J, Kohannim O, Gargalovic PS, Lusis AJ · Journal of Immunology 182(1):466-76 2009
    used by ATF3 (P18847) - the one cascade member the DOT1L inhibitor hits HARDER than the menin inhibitor, and a transcriptional REPRESSOR being counted as a stress output, 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, CHAC1 / BOTCH (Q9BUX1) - the largest single effect in the whole menin-inhibitor response (-5.11 log2) and a glutathione-degrading pro-apoptotic enzyme, named nowhere in this graph until now, 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
13. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19443658
    Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10-positive leukemias.

    Lin YH, et al. · Blood 2009
    used by Bite-back: a DOT1L inhibitor in CALM-AF10 deepens a genome-wide H3K79 deficit that already causes chromosome breaks, CALM-AF10 strips H3K79 methylation from the rest of the genome while adding it at HOXA - one fusion, two opposite effects on the same mark
14. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19228930
    Menin regulates the function of hematopoietic stem cells and lymphoid progenitors

    Maillard I, Chen YX, Friedman A, Yang Y, Tubbs AT, Shestova O, Pear WS, Hua X · Blood 2009
    used by Bone marrow haematopoietic stem cell — the postnatal comparator, and why the same fusion behaves differently here, MEN1 / menin — the adaptor the fusion cannot work without, Menin is dispensable for blood at rest and required for blood under stress - and that is a cell state, not a hedge, The stem-like self-renewal state — a limited stem-cell module grafted onto a committed cell
15. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19516257
    Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment

    Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ · Nature 2009
    used by Bone-marrow adipocyte — the fat cell that suppresses normal blood formation and feeds leukaemia a chemoresistance signal
16. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19812244
    Brd4 marks select genes on mitotic chromatin and directs postmitotic transcription.

    Dey A, Nishiyama A, Karpova T, McNally J, Ozato K · Mol Biol Cell 2009
    used by BRD4 — the best-drugged protein in this beat, and the one whose clinical result is already in and disappointing
17. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19575011
    CDK9 directs H2B monoubiquitination and controls replication-dependent histone mRNA 3'-end processing.

    Pirngruber J, Shchebet A, Schreiber L, et al. · EMBO Rep 2009
    used by CDK9 - the kinase the whole SEC story runs through, which this graph held only as half of a two-protein summary entry
18. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 19844166
    Insights into the function of the human P-TEFb component CDK9 in the regulation of chromatin modifications and co-transcriptional mRNA processing.

    Pirngruber J, Shchebet A, Johnsen SA · Cell Cycle 2009
    used by CDK9 - the kinase the whole SEC story runs through, which this graph held only as half of a two-protein summary entry
19. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19837270
    Homozygous deletion of CDKN2A (p16, p14) and CDKN2B (p15) genes is a poor prognostic factor in adult but not in childhood B-lineage acute lymphoblastic leukemia: a comparative deletion and hypermethylation study.

    · Cancer Genet Cytogenet 2009
    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
20. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19129520
    Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia

    Mullighan CG, Su X, Zhang J, Radtke I, Phillips LAA, Miller CB, Ma J, Liu W, Cheng C, Schulman BA, et al. · New England Journal of Medicine 2009
    used by Children's Oncology Group — the trial network, the AALL protocol series and the biobank that no single lab can substitute, NCI TARGET — a finished paediatric leukaemia genomics resource, not an active partner
21. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19182210
    Functional involvement of RINF, retinoid-inducible nuclear factor (CXXC5), in normal and tumoral human myelopoiesis.

    Pendino F, Nguyen E, et al. · Blood 2009
    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
22. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18945964
    Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors.

    Montesinos P, Bergua JM, Vellenga E, Rayon C, Parody R, de la Serna J, Leon A, Esteve J, Milone G, Deben G, Rivas C, Gonzalez M, Tormo M, Diaz-Mediavilla J, Gonzalez JD, Negri S, Amutio E, Brunet S, Lowenberg B, Sanz MA · Blood 2009
    used by Differentiation syndrome is the one human pharmacodynamic readout KMT2A-rearranged leukaemia already shares with APL - and in APL it is a complication of a cure, while here it is a complication of a 30% response rate
23. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19651892
    A role of histone H3 lysine 4 methyltransferase components in endosomal trafficking.

    Xu Z, Gong Q, Xia B, Groves B, Zimmermann M, Mugler C, Mu D, Matsumoto B, Seaman M, Ma D · J Cell Biol 2009
    used by DPY30 has a second job at the trans-Golgi network, and the authors who found it could not put ASH2L or RBBP5 there
24. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19147408
    Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia

    Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D, et al., Campana D · Lancet Oncology 2009
    used by Early T-cell precursor (ETP) — the thymocyte that has not yet given up being myeloid, and where KMT2A-rearranged T-ALL sits
25. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19749764
    Transcription elongation factor ELL2 directs immunoglobulin secretion in plasma cells by stimulating altered RNA processing.

    Martincic K, Alkan SA, Cheatle A, Borghesi L, Milcarek C · Nat Immunol 2009
    used by ELL2 — a SEC subunit that almost no cell needs, next to a paralogue almost every cell needs, Plasma cell - the end of the B lineage, and the only cell type in which ELL2 has a documented job
26. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19185337
    Elongator controls the migration and differentiation of cortical neurons through acetylation of alpha-tubulin.

    Creppe C, Malinouskaya L, et al. · Cell 2009
    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
27. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 19429107
    ELP3 localises to mitochondria and actin-rich domains at edges of HeLa cells.

    Barton D, Braet F, et al. · Neurosci Lett 2009
    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
28. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18996918
    Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration.

    Simpson CL, Lemmens R, et al. · Hum Mol Genet 2009
    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
29. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19665789
    A novel MLL-AF1p/Eps15 fusion variant in therapy-related acute lymphoblastic leukemia, lacking the EH-domains

    Shinohara A, Ichikawa M, Ueda K, Takahashi T, Hangaishi A, Kurokawa M · Leukemia Research 2009
    used by EPS15 (AF1p): the EH domains may or may not be discarded, and either way nobody has shown it matters, EPS15 / AF1p — domain architecture, and the one coordinate nobody has published, KMT2A::EPS15 (MLL-AF1p), t(1;11)(p32;q23) — the infant-ALL cytoplasmic partner
30. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19287094
    The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells

    Ford AM, Palmi C, Bueno C, Hong D, Cardus P, Knight D, Cazzaniga G, Enver T, Greaves M · J Clin Invest 2009
    used by ETV6::RUNX1 (TEL-AML1), t(12;21)(p13;q22)
31. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19151750
    O-GlcNAcylation is involved in the transcriptional activity of EWS-FLI1 in Ewing's sarcoma

    Bachmaier R, Aryee DN, Jug G, Kauer M, Kreppel M, Lee KA, Kovar H · Oncogene 28:1280-4 2009
    used by EWSR1::FLI1 has no residue-resolved, fusion-demonstrated PTM in its retained portion - every mapped site falls past the breakpoint, and the one site shown on the fusion has no residue
32. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19350351
    Possible involvement of RasGRP4 in leukemogenesis.

    Watanabe-Okochi N, Oki T, Komeno Y, et al. · Int J Hematol 2009
    used by Experiment — is a KMT2A-septin fusion menin-dependent? The one-plate version, Menin dependence of a non-elongation KMT2A fusion has never been demonstrated — the counted absence, and what the pivotal trial actually enrolled
33. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19166587
    SET-NUP214 fusion in acute myeloid leukemia- and T-cell acute lymphoblastic leukemia-derived cell lines.

    Quentmeier H, et al. · J Hematol Oncol 2009
    used by Experiment: blot menin in a SET-NUP214 immunoprecipitate, then run a menin inhibitor and selinexor alone and combined in LOUCY and MEGAL, 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, 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
34. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19029444
    Acute myeloid leukemia induced by MLL-ENL is cured by oncogene ablation despite acquisition of complex genetic abnormalities

    Horton SJ, Walf-Vorderwulbecke V, Chatters SJ, et al. (Williams O, senior author) · Blood 113(20):4922-4929 2009
    used by 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?, The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential
35. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19763085
    E2F1 mediates DNA damage and apoptosis through HCF-1 and the MLL family of histone methyltransferases.

    Tyagi S, Herr W · The EMBO Journal 2009
    used by Experiment: put four residues back - the minimal add-back control the PHD3 result has never had
36. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19854140
    Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes.

    Choudhary C, Olsen JV, Brandts C, Cox J, Reddy PN, Bohmer FD, Gerke V, Schmidt-Arras DE, Berdel WE, Muller-Tidow C, Mann M, Serve H · Mol Cell 2009
    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
37. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19620250
    Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia.

    Harding B, Lemos MC, Reed AA, Walls GV, Jeyabalan J, Bowl MR, et al. · Endocrine-Related Cancer 2009
    used by Four different ways to lose menin, and the graph has been treating them as one, Hypothesis: the PTH rise on menin inhibitors is on-target and exposure-dependent, not renal, The parathyroid does not need the rest of the body: deleting menin only there causes neoplasia and hypercalcaemia
38. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 21637673
    MLL leukemia-associated rearrangements in peripheral blood lymphocytes from healthy individuals

    Brassesco MS, Montaldi AP, Gras DE, de Paula Queiroz RG, Martinez-Rossi NM, Tone LG, Sakamoto-Hojo ET · Genetics and Molecular Biology 2009
    used by Fusion-positive clones that never become leukaemia: persistence in remission, spontaneous clearance, and silent rearrangements in healthy people, Hypothesis: the KMT2A break can be prevented rather than the fusion treated - stated so it can be killed, and it probably should be, What fraction of fusion-positive newborns ever get leukaemia? For ETV6::RUNX1, very few. For KMT2A, nobody knows, and the biology says the answer may be most of them
39. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19834960
    Impact of radiation and chemotherapy on risk of dental abnormalities: a report from the Childhood Cancer Survivor Study

    Kaste SC, Goodman P, Leisenring W, Stovall M, Hayashi RJ, Yeazel M, Beiraghi S, Hudson MM, Sklar CA, Robison LL, Baker KS · Cancer 2009
    used by Growth and endocrine consequences of being treated for leukemia as a baby
40. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19410543
    RAD6-Mediated transcription-coupled H2B ubiquitylation directly stimulates H3K4 methylation in human cells.

    Kim J, Guermah M, McGinty RK, Lee JS, Tang Z, Milne TA, Shilatifard A, Muir TW, Roeder RG · Cell 2009
    used by H2BK120ub (H2Bub1) — the ubiquitin tag on histone H2B that licenses H3K79 methylation, and the mark this graph was missing, PAF1C couples transcription to H2B ubiquitination - but the RTF1 half of that coupling is yeast-specific and contested in human cells, and PAF1C is one of the few complexes that genuinely binds the retained KMT2A fragment, The other arm of the crosstalk: H2Bub licenses H3K4 methylation through ASH2L and relieves a built-in COMPASS autoinhibition — and MLL3 does not respond at all, UBE2A (RAD6A) — the E2 for H2B ubiquitination in one primary account, contradicted by another, and with no KMT2A literature at all
41. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19574390
    Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing.

    Webby CJ, Wolf A, Gromak N, Dreger M, et al. · Science 2009
    used by 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
42. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19128795
    Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation

    Cui K, Zang C, Roh TY, et al. · Cell Stem Cell 2009
    used by H4K20me1 - the transcription- and replication-linked H4 state, whose gene-body level tracks Pol II; it HAS been profiled genome-wide in human haematopoietic stem cells twice, and a query scoped to 'leukemia' cannot see either dataset
43. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19129762
    Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter

    Chen MJ, Yokomizo T, Zeigler BM, Dzierzak E, Speck NA · Nature 2009
    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
44. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19796619
    Human placenta is a potent hematopoietic niche containing hematopoietic stem and progenitor cells throughout development

    Robin C, Bollerot K, Mendes S, Haak E, Crisan M, Cerisoli F, Lauw I, Kaimakis P, Jorna R, Vermeulen M, Kayser M, van der Linden R, Imanirad P, Verstegen M, Nawaz-Yousaf H, Papazian N, Steegers E, Cupedo T, Dzierzak E · Cell Stem Cell 2009
    used by Haemogenic endothelium — the vessel-wall cell that gives birth to blood
45. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19144990
    A myelopoiesis-associated regulatory intergenic noncoding RNA transcript within the human HOXA cluster

    Zhang X, Lian Z, Padden C, Gerstein MB, Rozowsky J, Snyder M, Gingeras TR, Kapranov P, Weissman SM, Newburger PE · Blood 113(11):2526-34 2009
    used by HOTAIRM1 lncRNA — the myeloid-differentiation transcript at the 3' end of HOXA, with a KMT2A-r evidence gap
46. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19912651
    Proteomic identification of heterogeneous nuclear ribonucleoprotein L as a novel component of SLM/Sam68 Nuclear Bodies.

    Rajan P, Dalgliesh C, Bourgeois CF, Heiner M, Emami K, Clark EL, Bindereif A, Stevenin J, Robson CN, Leung HY, Elliott DJ · BMC Cell Biol 2009
    used by KHDRBS1 (Sam68) — an RNA-binding protein that holds the MLL-AF4 message DOWN, a class no dropout screen can find
47. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19608861
    Lysine acetylation targets protein complexes and co-regulates major cellular functions

    Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M · Science 325(5942):834-40 2009
    used by KMT2A K1130 acetylation - the clock-controlled, SIRT1-erased site that every KMT2A fusion retains, 17 residues from the CXXC and 208 from the breakpoint, The 2015 paper did not discover the KMT2A acetylation site - it inherited it from the 2009 Choudhary acetylome, which was run in a cell panel that includes MV4-11, a KMT2A::AFF1 line
48. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19445675
    Both SEPT2 and MLL are down-regulated in MLL-SEPT2 therapy-related myeloid neoplasia.

    Cerveira N, Santos J, Bizarro S, et al. · BMC Cancer 2009
    used by KMT2A::SEPTIN2 (MLL-SEPT2), t(2;11)(q37;q23) — the therapy-related septin
49. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19144982
    The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group.

    Burmeister T, Meyer C, Schwartz S, Hofmann J, Molkentin M, Kowarz E · Blood 2009
    used by KMT2A::TET1 (MLL-LCX), t(10;11)(q22;q23) — the fusion that throws away a second CXXC domain
50. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19060922
    Alterations of the CxxC domain preclude oncogenic activation of mixed-lineage leukemia 2.

    Bach C, Mueller D, Buhl S, Garcia-Cuellar MP, Slany RK · Oncogene 2009
    used by KMT2B (MLL2/MLL4) - the other protein menin binds, and the one this graph never wrote, Necessary is not explanatory: four different questions that a knockout answers as if they were one, The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential, The MLL3/4-UTX switch fails to throw — menin inhibition kills by turning something ON, and cells that cannot turn it on survive, When a family shares a complex, the result is family-selective, not member-selective - the protein version of this graph's inhibitor-class rule
51. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19906723
    A capping-independent function of MePCE in stabilizing 7SK snRNA and facilitating the assembly of 7SK snRNP

    Xue Y, Yang Z, Chen R, Zhou Q · Nucleic Acids Research 38(2):360-9 2009
    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, MEPCE - absent from this graph until now, and a deeper pan-dependency than BRD4, MEPCE caps 7SK before assembly and then stops being an enzyme inside the particle - so its epigenetics annotation is a methyltransferase that methylates an RNA phosphate, which is exactly the case a mark-name regex mislabels in both directions, The 7SK snRNP - a stable RNA core with a reversibly docked kinase, which is why the reservoir is a switch and not a sink
52. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19657114
    Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol.

    van der Linden MH, Valsecchi MG, De Lorenzo P, Moricke A, Janka G, Leblanc TM, et al. · Blood 2009
    used by Leukaemia diagnosed in the first month of life: a different presentation and a different prognosis, When infant leukaemia comes back, it comes back early and while treatment is still running
53. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19631530
    Design, syntheses, and evaluation of Taspase1 inhibitors

    Lee JT, Chen DY, Yang Z, Ramos AD, Hsieh JJ-D, Bogyo M · Bioorganic & Medicinal Chemistry Letters 19(17):5086-5090 2009
    used by Lost from the KMT2A half: both taspase1 cleavage sites (D2666 and D2718) - the fusion is never processed
54. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19841675
    Structural studies of a four-MBT repeat protein MBTD1

    Eryilmaz J, Pan P, Amaya MF, et al. · PLoS ONE 2009
    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
55. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19049968
    MED19 and MED26 are synergistic functional targets of the RE1 silencing transcription factor in epigenetic silencing of neuronal gene expression.

    Ding N, Tomomori-Sato C, Sato S, et al. (6 authors; senior author Boyer TG) · J Biol Chem 2009
    used by MED19 - the Mediator subunit curated against an engineered MLL-AFF4 fusion protein, and the one REST uses to deliver G9a
56. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19592390
    MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations.

    Le Meur N, Holder-Espinasse M, Jaillard S, Goldenberg A, Joriot S, Amati-Bonneau P, et al. · Journal of Medical Genetics 2009
    used by MEF2C — an output-program transcription factor, the second-strongest leukemia co-dependency, and a gene humans cannot spare one copy of
57. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19169261
    Regulation of lymphoid versus myeloid fate 'choice' by the transcription factor Mef2c.

    Stehling-Sun S, Dade J, Nutt SL, DeKoter RP, Camargo FD · Nat Immunol 2009
    used by MEF2C — an output-program transcription factor, the second-strongest leukemia co-dependency, and a gene humans cannot spare one copy of
58. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19779455
    PARP-1 transcriptional activity is regulated by sumoylation upon heat shock.

    Martin N, Schwamborn K, Schreiber V, Werner A, Guillier C, Zhang XD, Bischof O, Seeler JS, Dejean A · EMBO J 2009
    used by MEN1-PIAS4 - DECLINED. The single supporting publication is a PARP-1 heat-shock sumoylation study in which menin is never named, and the row is a HeLa co-IP passenger
59. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19188669
    Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization

    Popovic R, Riesbeck LE, Velu CS, Chaubey A, Zhang J, Achille NJ, Erfurth FE, Eaton K, Lu J, Grimes HL, Chen J, Rowley JD, Zeleznik-Le NJ · Blood 113(14):3314-22 2009
    used by miR-196b — the HOXA-cluster microRNA that is a direct KMT2A-fusion target and a genuine double agent
60. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18923441
    Identification of new microRNA genes and aberrant microRNA profiles in childhood acute lymphoblastic leukemia

    Schotte D, Chau JCK, Sylvester G, Liu G, Chen C, van der Velden VHJ, Broekhuis MJC, Peters TCJM, Pieters R, den Boer ML · Leukemia 23(2):313-22 2009
    used by miR-196b — the HOXA-cluster microRNA that is a direct KMT2A-fusion target and a genuine double agent
61. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.journal-articlePMID 20064463
    A reconfigured pattern of MLL occupancy within mitotic chromatin promotes rapid transcriptional reactivation following mitotic exit.

    Blobel GA, Kadauke S, Wang E, et al. · Mol Cell 2009
    used by MLL1 stays on condensed mitotic chromosomes and tethers menin there — a menin-dependent function absent from this graph until cycle 34
62. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 19380030
    Cryptic insertion into 11q23 of MLLT10 not involved in t(1;15;11;10)(p36;q11;q23;q24) in infant acute biphenotypic leukemia.

    Matsuda K, Tanaka M, Araki S, et al. · Cancer Genet Cytogenet 2009
    used by MRD by genomic breakpoint: the only assay in this disease that is fusion-specific by construction
63. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19033443
    MSL2 promotes Mdm2-independent cytoplasmic localization of p53.

    Kruse JP, Gu W · J Biol Chem 2009;284:3250-3263 2009
    used by MSL2 — the second H2B ubiquitin ligase, sitting inside the MOF complex the KMT2A fragment contacts
64. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19545284
    Distribution of NPM1-ALK and X-ALK fusion transcripts in paediatric anaplastic large cell lymphoma: a molecular-histological correlation

    Damm-Welk C, Klapper W, Oschlies I, et al. · British Journal of Haematology 2009
    used by NPM1::ALK (NPM-ALK), t(2;5)(p23;q35)
65. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19356704
    Liver X receptor beta with mutations in the activation function-2 region is excluded from the nucleolus.

    Lall R, Kuruvilla S, Prüfer K · Cell Biol Int 2009
    used by NR1H2 / LXR-beta - the paralogue arm of the menin-LXR contact, present in both species and absent from the paper's conclusion, NR1H3 / LXR-alpha - the best-observed of the three MEN1 sterol partners, with both directions curated in two species, and menin as its corepressor
66. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19268590
    PALB2 links BRCA1 and BRCA2 in the DNA-damage response.

    Zhang F, et al. · Curr Biol 2009
    used by PALB2 (Q86YC2, 1,186 aa) - the physical link that makes BRCA1 and BRCA2 one pathway, named in 4 entries and never written; DepMap mean -0.339, statistically indistinguishable from CBX1 and MEN1, and its entire KMT2A intersection is one Ewing sarcoma germline paper
67. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19144573
    Delocalization of nucleolar poly(ADP-ribose) polymerase-1 to the nucleoplasm and its novel link to cellular sensitivity to DNA damage.

    Rancourt A, Satoh MS · DNA Repair (Amst) 2009
    used by PARP1 - the target whose inhibitors this disease was specifically shown to resist, and which three later papers combine anyway
68. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19956800
    Misguided transcriptional elongation causes mixed lineage leukemia

    Mueller D, Garcia-Cuellar MP, Bach C, Buhl S, Maethner E, Slany RK · PLoS Biology 7(11):e1000249 2009
    used by Plain-English: what transcription elongation is, and why a traffic light explains this leukemia, Step 3 — The hijack: the fusion drags the super elongation complex to paused RNA polymerase II, Step 6 — The consequence: self-renewal held on, differentiation never fires
69. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19409520
    Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder.

    Waltes R, Kalb R, Gatei M, et al. · American Journal of Human Genetics 2009
    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
70. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19586903
    The RNA-binding motif protein 15B (RBM15B/OTT3) acts as cofactor of the nuclear export receptor NXF1.

    Uranishi H, Zolotukhin AS, Lindtner S, Warming S et al. · J Biol Chem 2009
    used by RBM15 — m6A adaptor, AMKL fusion partner, and a named hit in the only KMT2A-biased RNA-protein CRISPR screen, RBM15B — the bridge from the DOT1L mark to the RNA layer: it reads H3K79me2 and steers m6A to start codons
71. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19786495
    Nuclear export factor RBM15 facilitates the access of DBP5 to mRNA.

    Zolotukhin AS, Uranishi H, Lindtner S, Bear J et al. · Nucleic Acids Res 2009
    used by RBM15 — m6A adaptor, AMKL fusion partner, and a named hit in the only KMT2A-biased RNA-protein CRISPR screen
72. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19759903
    SBDS expression and localization at the mitotic spindle in human myeloid progenitors.

    Orelio C, Verkuijlen P, Geissler J, van den Berg TK et al. · PLoS One 2009
    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
73. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19270695
    Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction.

    Gao D, Inuzuka H, Tseng A, Chin RY et al. · Nat Cell Biol 2009
    used by SKP2 - the substrate receptor that grips the retained fragment; two nodes in this graph already pointed at it as a free-text string with nothing to point to
74. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19822671
    Differential regulation of telomere and centromere cohesion by the Scc3 homologues SA1 and SA2, respectively, in human cells.

    Canudas S, Smith S · J Cell Biol 2009
    used by STAG2 - the cohesin subunit that defines secondary AML, and the one whose loss a KMT2A fusion does not care about
75. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18999987
    The anticancer agent chaetocin is a competitive substrate and inhibitor of thioredoxin reductase.

    Tibodeau JD, Benson LM, Isham CR, Owen WG, et al. · Antioxidants & Redox Signaling 2009
    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
76. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19426707
    TAF15 and the leukemia-associated fusion protein TAF15-CIZ/NMP4 are cleaved by caspases-3 and -7.

    Alves J, Wurdak H, Garay-Malpartida HM, Harris JL, Occhiucci JM, Belizario JE, Li J · Biochem Biophys Res Commun 2009
    used by TAF15 (RBP56, TAF2N) - the FET-family, prion-like partner that donates a low-complexity N-terminus to ZNF384
77. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19282835
    Increased risk for CNS relapse in pre-B cell leukemia with the t(1;19)/TCF3-PBX1

    Jeha S, Pei D, Raimondi SC, Onciu M, Campana D, Cheng C, Sandlund JT, Ribeiro RC, Rubnitz JE, Howard SC, Downing JR, Evans WE, Relling MV, Pui CH · Leukemia 2009
    used by TCF3::PBX1 (E2A-PBX1), t(1;19)(q23;p13.3)
78. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19372391
    Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1.

    Tahiliani M, Koh KP, et al. · Science 2009
    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
79. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19478948
    Selective killing of tumors deficient in methylthioadenosine phosphorylase: a novel strategy.

    Lubin M, Lubin A · PLoS One 2009
    used by The MTAP-deleted, MTA-high state - a genotype-imposed metabolic state that this project's KMT2A-rearranged arm turns out NOT to have, and that its own screen could never have detected directly
80. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19667127
    Histone H2BK123 monoubiquitination is the critical determinant for H3K4 and H3K79 trimethylation by COMPASS and Dot1.

    Nakanishi S, Lee JS, Gardner KE, Gardner JM, Takahashi YH, Chandrasekharan MB, Sun ZW, Osley MA, Strahl BD, Jaspersen SL, Shilatifard A · J Cell Biol 2009
    used by The trans-histone crosstalk H2Bub → DOT1L → H3K79me: modulatory for me1, effectively required for me2/me3
81. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19128791
    p53 regulates hematopoietic stem cell quiescence.

    Liu Y, Elf SE, Miyata Y, Sashida G, Liu Y, Huang G, Di Giandomenico S, Lee JM, Deblasio A, Menendez S, Antipin J, Reva B, Koff A, Nimer SD · Cell Stem Cell 2009
    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
82. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19917254
    Suppression of cancer cell growth by promoting cyclin D1 degradation.

    Shan J, Zhao W, Gu W · Mol Cell 2009
    used by USP2 (ubiquitin carboxyl-terminal hydrolase 2) - the ninth commonest KMT2A partner and the only one that is a deubiquitinase
83. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19405135
    Progressive neurocognitive impairment in young adult survivors of childhood acute lymphoblastic leukemia

    Harila MJ, Winqvist S, Lanning M, Bloigu R, Harila-Saari AH · Pediatric Blood & Cancer 2009
    used by What the treated brain looks like later: neurocognitive late effects after CNS-directed therapy in infancy
84. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19212338
    Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol.

    Van der Velden VH, Corral L, Valsecchi MG, et al. · Leukemia 2009
    used by Which MRD timepoint drives which decision in infant ALL, and how good the evidence for each is
85. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18299449
    The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia.

    Van Vlierberghe P, et al. · Blood 2008
    used by A counted PubMed absence is bounded by ABSTRACTS, not by papers - and the measurement you are looking for is usually a supporting figure, 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, Experiment: blot menin in a SET-NUP214 immunoprecipitate, then run a menin inhibitor and selinexor alone and combined in LOUCY and MEGAL, 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, 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 adult T-ALL is gamma-delta-lineage-restricted and resistant to steroids and chemotherapy early - the same cell state CALM-AF10 occupies, 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, 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), 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 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, Three addresses, one output: what SET::NUP214 actually does to the menin-interface hypothesis, and why it is a weaker test than CALM-AF10, Why this one rare leukaemia was thought to decide an argument about a drug used in a commoner one - and why it decides less than the title says (corrected 2026-09-21)
86. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18598942
    Menin critically links MLL proteins with LEDGF on cancer-associated target genes

    Yokoyama A, Cleary ML · Cancer Cell 14:36-46 2008
    used by 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, 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, Does the menin co-dependency survive lineage adjustment? (run), 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, Four days after the fusion is destroyed, menin signal at non-fusion promoters is 27% higher than control, Half the menin at fusion-occupied promoters is held by a tether that is not the fusion, KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23), LEDGF does NOT hold the fusion on chromatin: knocking it down INCREASES fusion occupancy, and an IBD-binding-dead fusion still binds its targets, Menin and LEDGF hold WILD-TYPE KMT2A on chromatin; for the fusion LEDGF is functionally required but positionally dispensable, 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, Menin's departure is partial where the fusion's loss is total, so the two are not stoichiometrically coupled, Michael Cleary (Stanford) & Akihiko Yokoyama (National Cancer Center, Tsuruoka) — the groups that discovered the menin requirement itself, Of the menin co-dependencies, which are actually safe to hit? (run), PSIP1 / LEDGF p75 — the tether with the best therapeutic index in the whole interactome, 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, The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential, The LEDGF IBD–KMT2A grip: the second half of the clamp, and nobody is drugging it, Where KMT2A and its fusions sit inside the nucleus — SNL1/SNL2, nuclear speckles and the condensate question, You can lower LEDGF without a LEDGF ligand: its protein half-life is about 4 hours against a proteome average of 20, so blocking guanine nucleotide or rRNA synthesis takes it out first
87. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18483194
    MLL protects CpG clusters from methylation within the Hoxa9 gene, maintaining transcript expression.

    Erfurth FE, Popovic R, Grembecka J, et al. · Proc Natl Acad Sci U S A 2008
    used by A published Kd is a property of five experimental choices, and this beat measured how much each one is worth, 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, Rerun the 2002 SPR with the two controls it did not have: cleave the GST, and put the protein on the chip instead of the DNA, 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, The MLL-protected Hoxa9 CpG sites bind the CXXC domain 4- to 9-fold tighter than the unprotected ones, in one ITC series at fixed everything else, The MT/BCB domain, Q03164 1147-1244: the CXXC fold plus a 41-residue basic tail nobody has measured on its own
88. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18559500
    Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating acinus and regulating cyclin A1

    Jang SW, Yang SJ, Ehlen A, et al. · Cancer Research 2008
    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
89. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17934517
    BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells

    French CA, Ramirez CL, Kolmakova J, et al. · Oncogene 2008
    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
90. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18676843
    Loss of MLL PHD finger 3 is necessary for MLL-ENL-induced hematopoietic stem cell immortalization.

    Chen J, Santillan DA, Koonce M, Wei W, Luo R, Thirman MJ, Zeleznik-Le NJ, Diaz MO · Cancer Res 2008
    used by 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., Audit, CORRECTED: the PHD add-back result was replicated in 2008 by a second group in a different fusion, and this graph already cited it, Experiment: put four residues back - the minimal add-back control the PHD3 result has never had, 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, Lost from the KMT2A half: PHD3 and the bromodomain are one cassette, not two modules (aa 1566-1765), 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
91. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18463634
    Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions

    Guelen L, Pagie L, Brasset E, Meuleman W, Faza MB, Talhout W, Eussen BH, de Klein A, Wessels L, de Laat W, van Steensel B · Nature 2008
    used by Analysis: does the fusion's target set sit at lamina-associated domain borders? A free overlay of published LAD maps on published fusion occupancy, The nuclear lamina and lamina-associated domains - evidence grade for KMT2A: weak and indirect, not none
92. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18206972
    A TFTC/STAGA module mediates histone H2A and H2B deubiquitination, coactivates nuclear receptors, and counteracts heterochromatin silencing.

    Zhao Y, Lang G, Ito S, Bonnet J, Metzger E, Sawatsubashi S, Suzuki E, Le Guezennec X, Stunnenberg HG, Krasnov A, Georgieva SG, Schüle R, Takeyama K, Kato S, Tora L, Devys D · Mol Cell 2008
    used by ATXN7L3 — the shared adaptor that actually sets H2Bub levels, and a KMT2A-selectivity hit nobody in this field has looked at, MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed, USP22 — a KMT2A-rearranged dependency that works through MEIS1 protein stability, and is not an interactor of the fusion
93. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18796627
    The PHD fingers of MLL block MLL fusion protein-mediated transformation

    Muntean AG, Giannola D, Udager AM, Hess JL · Blood 112(12):4690-3 2008
    used by Audit, CORRECTED: the PHD add-back result was replicated in 2008 by a second group in a different fusion, and this graph already cited it, Catalytic-dead UCH test: does KMT2A::USP2 need its deubiquitinase activity to transform?, Do different breaks give different biology? A verdict on partner identity vs breakpoint position, KMT2A exon 11 / intron 11 breakpoints (BCR subregion C): the infant, HOXA-low, topoisomerase-II-associated break, KMT2A major breakpoint cluster region (BCR1): intron 7 - exon 13, ~8.3 kb, KMT2A minor breakpoint cluster region (BCR2): intron 20 - exon 24, KMT2A::USP2, inv(11)(q23.3q23.3) - the minor-BCR fusion that keeps the PHD fingers, Menin inhibitors are prescribed on 'KMT2A-rearranged', a category that contains proteins as different as KMT2A::AFF1 and KMT2A::USP2, The "second breakpoint cluster region" of KMT2A (Meyer 2019): the founding report of BCR2, not a third cluster, The partner's deubiquitinase domain is what lets a PHD-retaining KMT2A fusion survive and transform
94. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 18800262
    Infant acute lymphoblastic leukemia: a 20-year children's hospital experience.

    Murray RA, Thom G, Gardner RV, Craver RD · Fetal Pediatr Pathol 2008
    used by Big liver, big spleen: the organomegaly numbers measured in infants, not pooled from children, CNS disease at diagnosis in infants: a real excess, measured by a procedure that partly creates it, The white cell count at diagnosis in infants, and why the reported medians disagree by fivefold
95. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19141473
    Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia

    Guenther MG, Lawton LN, Rozovskaia T, et al. (Young RA, senior author) · Genes & Development 22(24):3403-3408 2008
    used by Bivalent and primed chromatin at fusion target loci — and why the H3K4/H3K27 story is weaker than usually told, H3K4me2 - the LSD1 substrate, and the only histone mark ever compared head-to-head between two KMT2A fusion partners in human cells
96. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18406326
    The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription.

    LeRoy G, Rickards B, Flint SJ · Mol Cell 2008
    used by BRD3 - named in the founding BET paper's own mechanism and in one title since, and not once separated from BRD4 by any experiment in this disease
97. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 19383357
    The CALM and CALM/AF10 interactor CATS is a marker for proliferation.

    Archangelo LF, et al. · Mol Oncol 2008
    used by CALM-AF10 is predominantly cytoplasmic in transfected non-haematopoietic cells - and NUCLEAR in leukaemia cells (title corrected 2026-09-21; the five systems are five instances of one design)
98. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 18037964
    The leukemogenic CALM/AF10 fusion protein alters the subcellular localization of the lymphoid regulator Ikaros.

    Greif PA, et al. · Oncogene 2008
    used by CALM-AF10 is predominantly cytoplasmic in transfected non-haematopoietic cells - and NUCLEAR in leukaemia cells (title corrected 2026-09-21; the five systems are five instances of one design)
99. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18192237
    Role of CD34 antigen in myeloid differentiation of human hematopoietic progenitor cells.

    Salati S; Zini R; Bianchi E; Testa A; Mavilio F; Manfredini R; Ferrari S · Stem Cells 2008
    used by 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
100. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18827403
     Migratory localization of cyclin D2-Cdk4 complex suggests a spatial regulation of the G1-S transition.

     Wang Z, Xie Y, Zhang L, Zhang H, An X, Wang T, Meng A · Cell Struct Funct 2008
     used by CDK4 - the other half of the class name, and it is NOT the gene this disease needs
101. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 18082152
     Human CpG binding protein interacts with MLL1, MLL2 and hSet1 and regulates Hox gene expression

     Ansari KI, Mishra BP, Mandal SS · Biochimica et Biophysica Acta 1779(1):66-73 2008
     used by CXXC1 (CFP1) - a CpG-reading COMPASS subunit that binds MLL1 and recruits it to HoxA7, and whose CXXC domain cannot substitute for KMT2A's in a fusion
102. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18499258
     Dock10, a novel CZH protein selectively induced by interleukin-4 in human B lymphocytes.

     Yelo E, Bernardo MV, Gimeno L et al · Molecular Immunology 2008
     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
103. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 18835169
     DOCK10-mediated Cdc42 activation is necessary for amoeboid invasion of melanoma cells.

     Gadea G, Sanz-Moreno V, Self A et al · Current Biology 2008
     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
104. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18511943
     Nonprocessive methylation by Dot1 leads to functional redundancy of histone H3K79 methylation states.

     Frederiks F, Tzouros M, Oudgenoeg G, et al. · Nat Struct Mol Biol 2008
     used by DOT1L methylates H3K79 non-processively - so the three states are one distribution, not three signals, 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, 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
105. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 17984221
     Proline-rich transcript in brain protein induces stress granule formation.

     Kim JE, Ryu I, Kim WJ, Song OK, Ryu J, Kwon MY, Kim JH, Jang SK · Mol Cell Biol 2008
     used by EIF4G1 (Q04637) - a translation-initiation scaffold in the pan-MLL-fusion core, alone, with no other eIF4F subunit anywhere in the 960
106. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18838613
     A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups

     Sulong S, Moorman AV, Irving JAE, Strefford JC, Konn ZJ, Case MC, Minto L, Barber KE, Parker H, Wright SL, Stewart ARM, Bailey S, Bown NP, Hall AG, Harrison CJ · Blood 2008
     used by ETV6::RUNX1 (TEL-AML1), t(12;21)(p13;q22)
107. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 18927503
     Microsatellites are EWS/FLI response elements: genomic 'junk' is EWS/FLI's treasure.

     Gangwal K, Lessnick SL · Cell Cycle 2008
     used by EWS::FLI1 builds its own enhancers at GGAA microsatellites, and a single inherited base change that lengthens one repeat raises the fusion's binding and the patient's risk. KMT2A fusions occupy pre-existing, invariant CpG islands - which is why this disease has no germline modifier of its target set, and why its mouse models work at all.
108. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18626011
     Microsatellites as EWS/FLI response elements in Ewing's sarcoma

     Gangwal K, Sankar S, Hollenhorst PC, et al. · Proceedings of the National Academy of Sciences USA 2008
     used by EWSR1::FLI1 (EWS-FLI1), t(11;22)(q24;q12)
109. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18256599
     Haematopoietic stem cell release is regulated by circadian oscillations

     Mendez-Ferrer S, Lucas D, Battista M, Frenette PS · Nature 2008
     used by Experiment: block the beta-2 adrenergic receptor in a KMT2A-rearranged model — the leukaemogenic nerve signal runs through a receptor an old, cheap, infant-licensed drug already hits, Sympathetic nerve fibre in bone marrow — the wiring that sets the niche's daily rhythm, through beta-3 in health and beta-2 in leukaemia, The bone-marrow niche — the address a blood stem cell lives at, which 26 entries in this graph invoke and none had defined
110. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19056693
     HOXA9 is required for survival in human MLL-rearranged acute leukemias

     Faber J, Krivtsov AV, Stubbs MC, et al. · Blood 2008
     used by Experiment: combinatorial dose-titration of the HOXA9/MEIS1 program to find its minimal cut set, How much HOXA9 and MEIS1 is actually required? Partial dependence, a Hox code, and why this caps what any single target can do, HOXA-high versus HOXA-low KMT2A-rearranged leukemia — the split that breaks the one-mechanism story, HOXA10 - named in 27 entries as part of the HOXA output and never written; a posterior HOX paralogue that is regulated with HOXA9 and tested far less often, HOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it, Hypothesis: the fusion output program fails at a threshold on total cut-set suppression, so three nodes at 40% beat one node at 90%, MEF2C — an output-program transcription factor, the second-strongest leukemia co-dependency, and a gene humans cannot spare one copy of, MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed, Necessary is not explanatory: four different questions that a knockout answers as if they were one, PBX3 - the TALE cofactor the field says is non-redundant, and the experiment that says HOXA9 is the redundant one, Step 5 — The output program: HOXA9/HOXA10/MEIS1/PBX3 plus MEF2C, MYB, BCL2, FLT3 and PROM1/CD133, The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential, The PBX3-MEIS1 dimer, not HOXA9, is the unit that reproduces the MLL-fusion transcriptome - and it turns the HOXA cluster on from underneath
111. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19026781
     Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms.

     Margueron R; Li G; Sarma K; Blais A; Zavadil J; Woodcock CL; Dynlacht BD; Reinberg D · Mol Cell 2008
     used by EZH1 - the paralogue that makes the approved EZH2 drug the wrong drug for this disease
112. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18258493
     MEN1 and FANCD2 mediate distinct mechanisms of DNA crosslink repair.

     Marek LR, Kottemann MC, Glazer PM, Bale AE · DNA Repair (Amst) 2008
     used by FANCD2 — the FA effector menin binds, and the weakest FA gene in this graph's own selectivity scan, Fifth explanation for the Fanconi signal: it runs through menin binding FANCD2, not crosslink repair — tested, refuted, prior 0.07, Menin-FANCD2: one 2003 co-immunoprecipitation, a curated sufficient region of menin 214-390, and nothing since, The menin-FANCD2 bridge is dead: it was tested in 2008, the mutation spectra differ, and there is no genetic interaction
113. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 18550849
     HES1 is a novel interactor of the Fanconi anemia core complex.

     Tremblay CS, Huang FF, Habi O, Huard CC, Godin C, Lévesque G, Carreau M · Blood 2008
     used by FANCG — FA core complex; rank 27 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
114. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 19109563
     A role for MEIS1 in MLL-fusion gene leukemia

     Kumar AR, Li Q, Hudson WA, et al. · Blood 2008
     used by Fault trees, minimal cut sets and common-cause failure — reliability engineering on a buffered oncogenic program, How much HOXA9 and MEIS1 is actually required? Partial dependence, a Hox code, and why this caps what any single target can do, Hypothesis: the fusion output program fails at a threshold on total cut-set suppression, so three nodes at 40% beat one node at 90%, Step 6 — The consequence: self-renewal held on, differentiation never fires
115. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18829459
     Structure of WDR5 bound to mixed lineage leukemia protein-1 peptide.

     Patel A, Dharmarajan V, Cosgrove MS · J Biol Chem 2008
     used by Four ways a WDR5 result can be true and have nothing to do with KMT2A, Lost from the KMT2A half: the WIN motif and the whole WRAD interface (aa 3762-3767, Arg3765), The founding WRAD negative was never run on a fusion protein, WDR5 — the partner that is not a partner: it binds the half of KMT2A the fusion throws away, WDR5: an established wild-type KMT2A contact, and no fusion contact ever measured
116. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18395013
     Human fucosyltransferase IX: specificity towards N-linked glycoproteins and relevance of the cytoplasmic domain in intra-Golgi localization.

     Brito C, Kandzia S, Graça T, Conradt HS, Costa J · Biochimie 2008
     used by FUT9 - the dedicated Lewis-x synthase, structurally solved, and untouched by the KMT2A literature
117. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 17960638
     Graft versus leukemia effect after haploidentical HSCT in a MLL-negative infant AML with HLXB9/ETV6 rearrangement.

     Hauer J, Tosi S, Schuster FR, Harbott J, Kolb HJ, Borkhardt A · Pediatric Blood & Cancer 2008
     used by 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
118. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18806775
     Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy.

     Wang Z, et al. · Nature 2008
     used by GSK3 is required by KMT2A-rearranged leukaemia and nobody has shown it touches KMT2A
119. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18449190
     Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation.

     McGinty RK, Kim J, Chatterjee C, Roeder RG, Muir TW · Nature 2008
     used by H2BK120ub (H2Bub1) — the ubiquitin tag on histone H2B that licenses H3K79 methylation, and the mark this graph was missing, The trans-histone crosstalk H2Bub → DOT1L → H3K79me: modulatory for me1, effectively required for me2/me3
120. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18463162
     Signal-dependent regulation of transcription by histone deacetylase 7 involves recruitment to promyelocytic leukemia protein nuclear bodies.

     Gao C, et al. · Mol Biol Cell 2008;19:3020-7 2008
     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
121. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18977325
     H3K79 methylation profiles define murine and human MLL-AF4 leukemias.

     Krivtsov AV, Feng Z, Lemieux ME, Faber J, Vempati S, Sinha AU, Xia X, Jesneck J, Bracken AP, Silverman LB, Kutok JL, Kung AL, Armstrong SA · Cancer Cell 2008
     used by How much of this graph's mechanism is somebody else's fusion? A counted answer: 54% of fusion-bearing evidence, and 0% from a dedicated human KMT2A::AFF1 experiment, HOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it, Import class 1: murine MLL-AF9 myeloid transformation, the field's default assay and this graph's largest single import, Import class 4: human myeloid cell lines standing in for infant B-lymphoid disease, In KMT2A::AFF1 there is no oncogenic DOT1L unit: all H3K79 methylation is the endogenous MLLT10-directed activity, working on genes the fusion has opened, 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, Partner import: when a mechanism measured in one fusion is asserted about another, Step 4 — The histone mark: DOT1L and H3K79me2/3 at fusion target genes (and why global expression barely moves), The chain's biggest risk is generalising a myeloid mouse result to infant B-ALL, and the graph cannot measure how much of it does, The imports that were never necessary: H3K79 methylation in KMT2A::AFF1 has its own literature, and this graph barely cites it, The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential
122. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18281698
     LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated.

     Krueger BJ, Jeronimo C, Roy BB, Bouchard A, Barrandon C, Byers SA, Searcey CE, Cooper JJ, Bensaude O, Cohen EA, Coulombe B, Price DH · Nucleic Acids Res 2008
     used by How P-TEFb gets out of the reservoir: a dephosphorylation, a dissociation, and a reassembly on whichever scaffold is waiting, LARP7 - the clamp on the 3' end of 7SK, whose human loss-of-function phenotype is dwarfism and intellectual disability rather than cancer, Measure the free-versus-7SK-bound P-TEFb split in KMT2A::AFF1 cells - the experiment this whole beat turns on, which has never been done, The 7SK snRNP - a stable RNA core with a reversibly docked kinase, which is why the reservoir is a switch and not a sink
123. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18202658
     Identification of RPS14 as a 5q- syndrome gene by RNA interference screen

     Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N, Raza A, Root DE, Attar E, Ellis SR, Golub TR · Nature 2008
     used by Hypothesis: transfer-RNA and ribosome biology is a genuinely empty cell in KMT2A-rearranged leukemia, and translational capacity may be the unmeasured dependency
124. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18617636
     The Mll partial tandem duplication: differential, tissue-specific activity in the presence or absence of the wild-type allele

     Dorrance AM, Liu S, Chong A, Pulley B, Nemer D, Guimond M, Yuan W, Chang D, Whitman SP, Marcucci G, Caligiuri MA · Blood 2008
     used by KMT2A partial tandem duplication: an addition that only works once the normal copy has been switched off — 'recessive gain-of-function'
125. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 18337764
     Inv(11)(q21q23) fuses MLL to the Notch co-activator mastermind-like 2 in secondary T-cell acute lymphoblastic leukemia.

     Metzler M, Staege MS, Harder L, Mendelova D, Zuna J, Fronkova E, Meyer C, Flohr T, Bednarova D, Harbott J, Langer T, Gesk S, Trka J, Siebert R, Dingermann T, Marschalek R, Niemeyer C, Rascher W · Leukemia 2008
     used by KMT2A::MAML2, inv(11)(q21q23) - a therapy-related fusion that also causes a solid tumour
126. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 18656699
     A novel MLL-SEPT2 fusion variant in therapy-related myelodysplastic syndrome.

     Cerveira N, Santos J, Pinheiro M, et al. · Cancer Genet Cytogenet 2008
     used by KMT2A::SEPTIN2 (MLL-SEPT2), t(2;11)(q37;q23) — the therapy-related septin
127. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18483487
     The La-related protein LARP7 is a component of the 7SK ribonucleoprotein and affects transcription of cellular and viral polymerase II genes.

     Markert A, Grimm M, Martinez J, Wiesner J, Meyerhans A, Meyuhas O, Sickmann A, Fischer U · EMBO Rep 2008
     used by LARP7 - the clamp on the 3' end of 7SK, whose human loss-of-function phenotype is dwarfism and intellectual disability rather than cancer
128. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18794358
     Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes

     Ullah M, Pelletier N, Xiao L, Zhao SP, et al. · Mol Cell Biol 2008
     used by MEAF6 - a 191-residue subunit shared between the NuA4/TIP60 and MOZ/MORF acetyltransferase complexes, whose only two UniProt localisations both cite papers that are not localisation studies
129. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18326819
     The MADS transcription factor Mef2c is a pivotal modulator of myeloid cell fate.

     Schüler A, Schwieger M, Engelmann A, Weber K, Horn S, Müller U, Arnold MA, Olson EN, Stocking C · Blood 2008
     used by MEF2C — an output-program transcription factor, the second-strongest leukemia co-dependency, and a gene humans cannot spare one copy of
130. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18590796
     Relation between menin expression and NF-kappaB activity in an intestinal cell line.

     Theillaumas A, Blanc M, Couderc C, Poncet G, Manship B, Chayvialle JA, Roche C, Cordier-Bussat M · Mol Cell Endocrinol 2008
     used by Menin represses NF-kB transactivation — through a mapped central region, a SIRT1 cofactor, and an RPA2 off-switch, in every tissue except the one this project cares about
131. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18353770
     Inactivation of NuRD component Mta2 causes abnormal T cell activation and lupus-like autoimmune disease in mice.

     Lu X, Kovalev GI, Chang H, Kallin E, Knudsen G, Xia L, Mishra N, Ruiz P, Li E, Su L, Zhang Y · Journal of Biological Chemistry 2008
     used by MTA2 / MTA1L1 (O94776) - the NuRD scaffold that clamps HDAC1, recruited in T lymphocytes by BCL11B, and absent together with MTA1 and MTA3 from every column of the pan-MLL-fusion interactome
132. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 18772439
     A neoplastic gene fusion mimics trans-splicing of RNAs in normal human cells

     Li H, Wang J, Mor G, Sklar J · Science 2008
     used by Newborn screening for leukaemia fusions: verdict NOT FEASIBLE TODAY, and the reason is arithmetic plus the absence of anything to offer a positive, Trans-splicing: healthy human cells make cancer-associated fusion transcripts without any chromosome rearrangement
133. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18455126
     Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells.

     Chen W, Kumar AR, Hudson WA, et al. · Cancer Cell 2008
     used by Ordering the fusions developmentally — which stage of blood formation each one hijacks, and at what age the child presents
134. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18285464
     Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo

     Sarma K, Margueron R, Ivanov A, Pirrotta V, Reinberg D · Mol Cell Biol 2008
     used by PHF1 (PCL1) - the PRC2 accessory subunit whose Tudor domain reads H3K36me3, and the 3' acceptor shared by three different NuA4-donor fusions in two different tumour types
135. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 18299451
     Acute promyelocytic leukemia: from highly fatal to highly curable

     Wang ZY, Chen Z · Blood 2008
     used by PML — domain architecture and residue coordinates, RARA — domain architecture and residue coordinates
136. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18408733
     Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway

     Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L, Zhou J, Zhu J, Raught B, de Thé H · Nature Cell Biology 10:547-55 2008
     used by PML K160 SUMOylation - the retained-portion PTM that became an approved therapy, and the benchmark every other retained site should be measured against
137. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19029980
     Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation

     Nasr R, Guillemin MC, Ferhi O, Soilihi H, Peres L, Berthier C, Rousselot P, Robledo-Sarmiento M, Lallemand-Breitenbach V, Gourmel B, Vitoux D, Pandolfi PP, Rochette-Egly C, Zhu J, de The H · Nat Med 2008
     used by PML::RARA, t(15;17)(q24;q21), Why PML::RARA became curable — and what KMT2A::AFF1 does not share with it
138. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18157086
     Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation.

     Edmunds JW, Mahadevan LC, Clayton AL · EMBO J 2008
     used by SETD2 (Q9BYW2) - the H3K36 trimethyltransferase that binds all seven MLL fusions, and the only one of them with a published KMT2A::AFF1 dependency test
139. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 18445686
     EML3 is a nuclear microtubule-binding protein required for the correct alignment of chromosomes in metaphase.

     Tegha-Dunghu J, Neumann B, Reber S, Krause R et al. · J Cell Sci 2008
     used by SKIC8 (formerly WDR61) — the last PAF1C subunit, and a gene-symbol trap worth recording
140. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 19056941
     Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters.

     Core LJ, Waterfall JJ, Lis JT · Science 2008
     used by Strand-resolved transcription across the AFF1 / AFF1-AS1 / C4orf36 promoter - the only measurement that can say which gene the signal belongs to
141. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18480474
     Screening for antiviral inhibitors of the HIV integrase-LEDGF/p75 interaction using the AlphaScreen luminescent proximity assay.

     Hou Y, McGuinness DE, et al. · J Biomol Screen 2008
     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
142. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17906700
     Leukaemia lineage specification caused by cell-specific Mll-Enl translocations.

     Cano F, Drynan LF, Pannell R, et al. · Oncogene 2008
     used by The most faithful mouse models of t(11;19) are reciprocal-positive by design, and the commonest ones carry no reciprocal allele at all - and nobody has compared them
143. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 18510699
     Etoposide-initiated MLL rearrangements detected at high frequency in human primitive hematopoietic stem cells with in vitro and in vivo long-term repopulating potential

     Libura J, Ward M, Solecka J, Richardson C · European journal of haematology 2008
     used by 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
144. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18840606
     WDR5 interacts with mixed lineage leukemia (MLL) protein via the histone H3-binding pocket.

     Song JJ, Kingston RE · J Biol Chem 2008
     used by 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
145. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17551948
     Identification of a novel fusion gene MLL-MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23).

     Nemoto N, Suzukawa K, Shimizu S, Shinagawa A, Takei N, Taki T, Hayashi Y, Kojima H, Kawakami Y, Nagasawa T · Genes, Chromosomes & Cancer 2007
     used by 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 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
146. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17135274
     The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling.

     Bitoun E, Oliver PL, Davies KE · Hum Mol Genet 2007
     used by AFF1 / AF4 — the 3' half of the fusion, and a target with almost no structural footing
147. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17898714
     Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive.

     Guccione E, Bassi C, Casadio F, Martinato F, et al. · Nature 2007
     used by 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, PRMT6 - the enzyme whose mark is MUTUALLY EXCLUSIVE with the MLL complex on the H3 tail, and which shuts HOX genes down by evicting WDR5
148. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17500065
     PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex.

     Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, Ge K · Journal of Biological Chemistry 2007
     used by ASH2L — the WRAD subunit that has DPY30's essentiality profile and none of its co-dependency signal, DPY30: the founding negative does not cover it, and it has no KMT2A contact to lose, KDM6A / UTX — a commonly asserted KMT2A partner that belongs to a different complex and points the opposite way, The founding WRAD negative was never run on a fusion protein
149. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17410185
     Complex MLL rearrangements in t(4;11) leukemia patients with absent AF4.MLL fusion allele.

     Kowarz E, Burmeister T, Lo Nigro L, et al. · Leukemia 2007
     used by 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, Forty-five percent of t(4;11) patients express a KMT2A fusion transcript that keeps the whole WRAD interface, Infants whose leukaemia expresses the reciprocal fusion survive far better - 62.4% versus 11.7% event-free at four years, Reciprocal status is a different fact depending on whether you assay DNA or RNA, and the whole prognostic literature is RNA
150. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18371340
     Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss.

     Ruzankina Y, Pinzon-Guzman C, Asare A, Ong T, Pontano L, Cotsarelis G, Zediak VP, Velez M, Bhandoola A, Brown EJ · Cell Stem Cell 2007
     used by ATR - the replication-stress kinase with the best preclinical case in this disease and the best published reason not to inhibit it
151. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17908926
     Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions.

     Liu H, et al. · Genes Dev 2007
     used by ATR phosphorylates KMT2A at S516 to break the SCF(Skp2) contact - a phospho-gated degradation switch sitting inside the retained fragment, Attribution audit 2 of 5 - post-translational modifications on KMT2A::AFF1: nothing survives at peptide level, and the one strong PTM result is explicitly about the wild-type protein, 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, KMT2A / MLL1 — the gene that breaks, Knock a tag-plus-degron cassette into the endogenous KMT2A::AFF1 allele in SEM - one construct that makes five claim classes attributable, SCF(Skp2) grips the retained fragment and the fusion escapes it - the clearest documented non-menin contact on that region, SKP2 - the substrate receptor that grips the retained fragment; two nodes in this graph already pointed at it as a free-text string with nothing to point to, The experiment nobody has done: an epitope tag knocked into the endogenous KMT2A fusion allele in a patient-derived line, The five verdicts in one place, plus what this beat read and did not use, The non-synchronisable state: five KMT2A-rearranged lines refuse mimosine, double thymidine and nocodazole, and the fusion protein does not fluctuate through the cycle, The working attribution reagent in this literature is not an antibody, it is the gel - and that single fact predicts which claim classes survive, 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, Why PML::RARA became curable — and what KMT2A::AFF1 does not share with it
152. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16983345
     Transcription linked to recombination: a gene-internal promoter coincides with the recombination hot spot II of the human MLL gene.

     Scharf S, Zech J, Bursen A, et al. · Oncogene 2007
     used by 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, 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, Junction RT-PCR is the one routine assay in this disease that IS fusion-specific - and it is structurally blind to KMT2A*, KMT2A*: a menin-blind, LEDGF-blind, SET-competent KMT2A protein made from out-of-frame reciprocal alleles, MRD by fusion transcript: fast, standardised, partner-limited - and structurally blind to KMT2A*, 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
153. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     PDB entries 1IEP (Crystal structure of the c-Abl kinase domain in complex with STI-571; Mus musculus, UniProt P00520) and 2HYY (Human Abl kinase domain in complex with imatinib; Homo sapiens, UniProt P00519)

     RCSB Protein Data Bank · RCSB PDB 2007
     used by BCR::ABL1 (Philadelphia chromosome), t(9;22)(q34;q11)
154. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17975067
     Menin controls growth of pancreatic beta-cells in pregnant mice and promotes gestational diabetes mellitus.

     Karnik SK, Chen H, McLean GW, Heit JJ, Gu X, Zhang AY, et al. · Science 2007
     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, Hypothesis: the same drug is protective in the islet and harmful in the parathyroid and the growth plate, Menin is a brake the beta cell releases on purpose: pregnancy and glucose both lower it, 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
155. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17671196
     Interaction of MLL amino terminal sequences with menin is required for transformation.

     Caslini C, Yang Z, El-Osta M, Milne TA, Slany RK, Hess JL · Cancer Res 2007
     used by Bounded failure: a PMCID that exists and a body that does not - the MLL amino-terminus transformation paper is unreadable by both PMC routes, Menin dependence of a non-elongation KMT2A fusion has never been demonstrated — the counted absence, and what the pivotal trial actually enrolled
156. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17804713
     Expression of a CALM-AF10 fusion gene leads to Hoxa cluster overexpression and acute leukemia in transgenic mice.

     Caudell D, et al. · Cancer Res 2007
     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, PICALM::MLLT10 (CALM-AF10), t(10;11)(p13;q14) - the DOT1L-dependent HOXA fusion that contains no KMT2A, The focal half: H3K79 hypermethylation at the HOXA cluster and MEIS1 - but which cluster member differs between CALM-AF10 and MLL-AF10
157. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17923126
     Nucleolar localization of parafibromin is mediated by three nucleolar localization signals.

     Hahn MA, Marsh DJ · FEBS Lett 2007
     used by CDC73 / parafibromin — the PAF1C subunit that was genetically tested, and a second tumour suppressor required by the fusion
158. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 17332306
     Synergism between etoposide and 17-AAG in leukemia cells: critical roles for Hsp90, FLT3, topoisomerase II, Chk1, and Rad51.

     Yao Q, Weigel B, Kersey J · Clin Cancer Res 2007
     used by CHEK1 (CHK1) - the node where this graph's chidamide synergy actually lands, and the reason that synergy is an HR-impairment argument
159. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17713479
     IgH class switching and translocations use a robust non-classical end-joining pathway

     Yan CT, Boboila C, Souza EK, Rajewsky K, Alt FW, et al. · Nature 2007
     used by Class switch recombination: a B cell deliberately mutates and cuts its own antibody locus, and the same enzyme causes MYC-IgH translocations
160. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17609428
     The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells.

     van Rhenen A, van Dongen GA, Kelder A, Rombouts EJ, Feller N, Moshaver B, et al. · Blood 2007
     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
161. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18070935
     A human postnatal lymphoid progenitor capable of circulating and seeding the thymus

     Six EM, Bonhomme D, Monteiro M, Beldjord K, Jurkowska M, Cordier-Garcia C, et al., Andre-Schmutz I · Journal of Experimental Medicine 2007
     used by Common lymphoid progenitor (CLP) — the CD10-positive lymphoid route that infant KMT2A leukaemia appears NOT to take
162. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
     Interfant-06: International Collaborative Treatment Protocol for Infants Under One Year With Acute Lymphoblastic or Biphenotypic Leukemia (NCT00550992)

     · ClinicalTrials.gov 2007
     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, Dexamethasone - the steroid an infant is actually on for most of the protocol, and the one with a high-certainty neurodevelopmental signal in babies, Interfant-06 — 651 infants, and the definitive answer that myeloid-style consolidation does not help, Prednisolone - the active steroid, the drug every resistance experiment in this disease actually used, and the one given into the spinal fluid, Prednisone - the prophase drug, the prognostic factor, and a prodrug that has never itself been tested on a KMT2A-rearranged blast, The Interfant-06 backbone, phase by phase: what the protocol every infant reference in this graph points at actually does, 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, Which MRD timepoint drives which decision in infant ALL, and how good the evidence for each is
163. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17994099
     JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes.

     Frescas D, Guardavaccaro D, et al. · Nature 2007
     used by Degrade one CXXC reader, ChIP the fusion: the one experiment that settles whether the address is contested, KDM2B — 513 potent ChEMBL rows that are mostly patent bins, and no structure of the domain they claim to inhibit, 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
164. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17855633
     A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification.

     Mueller D, Bach C, Zeisig D, et al. · Blood 2007
     used by DOT1L and H3K79 in KMT2A::MLLT1: a direct partner contact, mutually exclusive with the elongation complex, and the only fusion with a DOT1L-inhibitor complete remission
165. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17588759
     The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein.

     Kowaljow V, Marcowycz A, Ansseau E, et al. · Neuromuscular Disorders 2007
     used by DUX4::IGH (IGH-DUX4), t(4;14)/ins(14;4) — D4Z4 repeat insertion into the IGH locus, Mechanism class 5 — enhancer hijacking (inv(3) GATA2/EVI1 — and DUX4-r, which only half belongs here)
166. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17044034
     Apoptosis induction and growth suppression by U19/Eaf2 is mediated through its ELL-binding domain

     Hahn J, Xiao W, Jiang F, Simone F, Thirman MJ, Wang Z · The Prostate 67(2):146-53 2007
     used by EAF2 (U19) — the EAF paralogue whose ELL-binding domain is a mapped tumour-suppressor module, described entirely in prostate cancer
167. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17353931
     Large-scale mapping of human protein-protein interactions by mass spectrometry.

     Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, et al. · Mol Syst Biol 2007
     used by EBF3 — a single large-scale MS hit against menin, in a B-lineage transcription factor family, which is the only reason it is worth recording, 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, RPRM (reprimo) - the other half of menin's Ewing 2007 pair, a protein with no experimental localisation at all, and a promoter methylated in 45% of paediatric AML
168. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17726105
     ALL1 fusion proteins induce deregulation of EphA7 and ERK phosphorylation in human acute leukemias

     Nakanishi H, Nakamura T, Canaani E, Croce CM · Proc Natl Acad Sci U S A 104:14442-7 2007
     used by EPHA7 - ephrin type-A receptor 7, a published direct promoter target of the ALL1/AF4 (KMT2A::AFF1) fusion protein, EPHA7 is the one core member with a published KMT2A::AFF1 promoter ChIP - and this beat's own data put it second on separation while denying it to the AF9 samples, The separation MARGIN, not the recurrence count, is the statistic that identifies a partner-specific promoter
169. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17332359
     Targeting the oligomerization domain of ETO interferes with RUNX1/ETO oncogenic activity in t(8;21)-positive leukemic cells

     Wichmann C, Chen L, Heinrich M, et al. · Cancer Research 2007
     used by Experiment (proposed) — cross-family interface point-mutant panel: is the obligate interface real in each fusion?, Hypothesis — forced-oligomerisation interfaces are the mutation-resistant drug targets the fusion field has been ignoring, Hypothesis — the menin lesson generalises: every non-enzymatic fusion has an obligate partner interface that is more druggable than the fusion, Mechanism class 2 — transcription-factor corruption (RUNX1::RUNX1T1, PML::RARA, ETV6::RUNX1, CBFB::MYH11) — a balance, not a pure dominant negative
170. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17396147
     FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway.

     Ling C, Ishiai M, Ali AM, Medhurst AL, Neveling K, Kalb R, Yan Z, Xue Y, Oostra AB, Auerbach AD, Hoatlin ME, Schindler D, Joenje H, de Winter JP, Takata M, Meetei AR, Wang W · EMBO J 2007
     used by FAAP100 — FA core complex; rank 36 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
171. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17412408
     Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair.

     Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D'Andrea AD, Elledge SJ · Cell 2007
     used by FANCI — ID2 module; rank 15 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
172. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17382112
     Decreased adult height in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study

     Chow EJ, Friedman DL, Yasui Y, Whitton JA, Stovall M, Robison LL, Sklar CA · The Journal of Pediatrics 2007
     used by Growth and endocrine consequences of being treated for leukemia as a baby
173. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17589499
     NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis.

     Wang GG, Cai L, Pasillas MP, Kamps MP · Nat Cell Biol 2007
     used by 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, NSD1 - the H3K36 dimethyltransferase whose catalytic activity a NUP98 fusion cannot do without, and which cells can otherwise lose almost for free, NUP98 — domain architecture and residue coordinates (with the 1817/920 numbering trap resolved), NUP98::NSD1, t(5;11)(q35;p15.5)
174. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17512414
     High-resolution profiling of histone methylations in the human genome.

     Barski A, Cuddapah S, Cui K, et al. · Cell 2007
     used by H3K79me1 - the first methyl group, the one H2B ubiquitination is not needed for, and the state HOX loci fall back to as blood cells mature, H3K79me3 - the third methyl group, the one that needs the most enzyme flux and the one human DOT1L makes least of
175. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 18079182
     PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation.

     Hyllus D, Stein C, Schnabel K, Schiltz E, et al. · Genes Dev 2007
     used by 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, 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, PRMT6 - the enzyme whose mark is MUTUALLY EXCLUSIVE with the MLL complex on the H3 tail, and which shuts HOX genes down by evicting WDR5
176. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17898715
     Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation.

     Kirmizis A, Santos-Rosa H, Penkett CJ, Singer MA, et al. · Nature 2007
     used by 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
177. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 17947579
     JMJD6 is a histone arginine demethylase.

     Chang B, Chen Y, Zhao Y, Bruick RK · Science 2007
     used by 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, 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
178. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17612494
     E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases.

     · Mol Cell 2007
     used by HCFC1 (HCF-1) — a founding member of the wild-type KMT2A complex that the fusion cannot bind
179. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17242198
     Definition of pRB- and p53-dependent and -independent steps in HIRA/ASF1a-mediated formation of senescence-associated heterochromatin foci.

     Ye X, et al. · Mol Cell Biol 2007;27:2452-65 2007
     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
180. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17637674
     Structural insight into filament formation by mammalian septins.

     Sirajuddin M, Farkasovsky M, Hauer F, et al. · Nature 2007
     used by How a cytoskeletal partner reaches chromatin at all — the KMT2A N-terminus drags it in, and the traffic runs both ways, SEPTIN11 (septin-11) — KMT2A fusion partner at 4q21, adjacent to AFF1, SEPTIN2 (septin-2 / NEDD5) — KMT2A fusion partner in t(2;11)(q37;q23), SEPTIN5 (septin-5 / CDCrel-1) — KMT2A fusion partner in t(11;22)(q23;q11.2), SEPTIN6 (septin-6) — cytoskeletal GTPase, KMT2A fusion partner in t(X;11)(q24;q23), SEPTIN9 (septin-9 / MSF) — cytoskeletal GTPase, KMT2A fusion partner in t(11;17)(q23;q25)
181. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17252016
     Spliced MLL fusions: a novel mechanism to generate functional chimeric MLL-MLLT1 transcripts in t(11;19)(q23;p13.3) leukemia.

     Meyer C, Burmeister T, Strehl S, Schneider B, et al. · Leukemia 2007
     used by How a spliced fusion works: the break lands in front of MLLT1, the gene is never cut, and there is nothing left to make a reciprocal product from, Nobody has ever stratified any KMT2A::MLLT1 outcome or drug-response analysis by reciprocal or spliced status - a measured absence, with the queries, Who the 460 KMT2A::MLLT1 patients actually are: 88% lymphoblastic, 53% infants, and only 47 cases of AML in the whole series
182. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17590169
     Age-related penetrance of endocrine tumours in multiple endocrine neoplasia type 1 (MEN1): a multicentre study of 258 gene carriers.

     Machens A, Schaaf L, Karges W, Frank-Raue K, Bartsch DK, Rothmund M, Schneyer U, Goretzki P, Raue F, Dralle H · Clin Endocrinol (Oxf) 67:613-22 2007
     used by How long does menin have to be gone? Two months in a mouse islet, a decade or more in a human carrier, Hypothesis: the PTH rise on menin inhibitors is on-target and exposure-dependent, not renal, Intact PTH rises in 34% of patients on revumenib, and hyperparathyroidism is on the label, Pancreatic neuroendocrine tumours in MEN1: the manifestation that kills, and the one the animal data points at, Pituitary adenoma in MEN1: the third manifestation, and the one that matters most for a growing child, Primary hyperparathyroidism in MEN1: the first and commonest consequence of losing menin
183. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17709395
     The transcription-dependent dissociation of P-TEFb-HEXIM1-7SK RNA relies upon formation of hnRNP-7SK RNA complexes.

     Barrandon C, Bonnet F, Nguyen VT, Labas V, Bensaude O · Mol Cell Biol 2007
     used by How P-TEFb gets out of the reservoir: a dephosphorylation, a dissociation, and a reassembly on whichever scaffold is waiting, The 7SK snRNP - a stable RNA core with a reversibly docked kinase, which is why the reservoir is a switch and not a sink
184. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17439948
     Identification of a HoxA10 activation domain necessary for transcription of the gene encoding beta3 integrin during myeloid differentiation

     Bei L, Lu Y, Bellis SL, Zhou W, Horvath E, Eklund EA · Journal of Biological Chemistry 282:16846-16859 2007
     used by HOXA10 - named in 27 entries as part of the HOXA output and never written; a posterior HOX paralogue that is regulated with HOXA9 and tested far less often
185. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17234739
     HOXA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development.

     Magnusson M, Brun AC, Miyake N, Larsson J, Ehinger M, Bjornsson JM, Wutz A, Sigvardsson M, Karlsson S · Blood 2007
     used by HOXA10 - named in 27 entries as part of the HOXA output and never written; a posterior HOX paralogue that is regulated with HOXA9 and tested far less often
186. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17646674
     Combinatorial effects of splice variants modulate function of Aiolos.

     Caballero R, Setien F, Lopez-Serra L, et al. · Journal of Cell Science 2007
     used by IKZF3 / Aiolos (Q9UKT9) - the B-lymphoid transcription factor that goes UP under both inhibitors, regulates BCL2, and is a degradable drug target
187. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17891136
     Protein arginine-methyltransferase-dependent oncogenesis.

     Cheung N, Chan LC, Thompson A, Cleary ML, So CW · Nat Cell Biol 2007
     used by Import class 5: evidence borrowed from fusions that are not KMT2A fusions at all, PRMT1 — an MLL-fusion cofactor whose first-in-human inhibitor was terminated for lack of efficacy and toxicity
188. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17658395
     A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial

     Pieters R, Schrappe M, De Lorenzo P, et al. · Lancet 2007
     used by Interfant-99 — the first global infant ALL protocol, and the first negative answer on myeloid intensification, Interfant-99 and Interfant-06: what they report about partners, and what they do not, 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, Leukaemia diagnosed in the first month of life: a different presentation and a different prognosis, Lymphoid-style versus myeloid-style consolidation — the question asked twice in 1,100 infants, and answered no both times, 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, The Interfant-06 backbone, phase by phase: what the protocol every infant reference in this graph points at actually does, 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 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
189. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.trial_registry
     Interfant-99 trial registration

     Dutch Childhood Oncology Group and Interfant consortium · ClinicalTrials.gov 2007
     used by Interfant-99 — the first global infant ALL protocol, and the first negative answer on myeloid intensification
190. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17625570
     Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer

     Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H · Nature 2007
     used by Is KMT2A::AFF1 leukemia epithelial or endothelial? No — it is haematopoietic. But the question is a good one
191. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17207460
     Diversity within the JMJD2 histone demethylase family.

     Shin S, Janknecht R · Biochem Biophys Res Commun 2007
     used by KDM4C (JMJD2C/GASC1) — recruited by the retained KMT2A N-terminus, drugged in a KMT2A::AFF1 line, and invisible to CRISPR
192. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18371366
     Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors.

     Jude CD, Climer L, Xu D, Artinger E, Fisher JK, Ernst P · Cell Stem Cell 2007
     used by KMT2A / MLL1 — the gene that breaks, Quiescence in the blood stem cell is actively held there by MLL1 - and losing MLL1 pushes the stem cell INTO cycle while pulling the progenitor OUT of it, The cell types that need MLL1 are the uncommitted ones - dependence ends exactly where lineage commitment begins, The two founding conditional Mll knockouts were published back to back and they do not agree: fatal marrow failure in three weeks, or grossly normal blood
193. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 18371367
     Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal.

     McMahon KA, Hiew SY, Hadjur S, Veiga-Fernandes H, Menzel U, Price AJ, Kioussis D, Williams O, Brady HJM · Cell Stem Cell 2007
     used by KMT2A / MLL1 — the gene that breaks, Quiescence in the blood stem cell is actively held there by MLL1 - and losing MLL1 pushes the stem cell INTO cycle while pulling the progenitor OUT of it, The two founding conditional Mll knockouts were published back to back and they do not agree: fatal marrow failure in three weeks, or grossly normal blood
194. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17145626
     Analysis of acute leukemias with MLL/ENL fusion transcripts: identification of two novel breakpoints in ENL

     Fu JF, Liang DC, Shih LY · American Journal of Clinical Pathology 2007
     used by KMT2A::MLLT1 (MLL-ENL), t(11;19)(q23;p13.3), Spliced and balanced KMT2A::MLLT1 do not automatically make the same oncoprotein - unless you restrict the comparison, which nobody has, The KMT2A::MLLT1 chimeric protein: exactly what survives the join on each side, in residue numbers, The reciprocal MLLT1::KMT2A transcript was reported in the paper that discovered KMT2A, and nobody has gone back to it in thirty-four years
195. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17574968
     A new subtype of MLL-SEPT2 fusion transcript in therapy-related acute myeloid leukemia with t(2;11)(q37;q23): a case report and literature review.

     van Binsbergen E, de Weerdt O, Buijs A · Cancer Genet Cytogenet 2007
     used by KMT2A::SEPTIN2 (MLL-SEPT2), t(2;11)(q37;q23) — the therapy-related septin
196. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17250889
     An MLL-SEPT9 fusion and t(11;17)(q23;q25) associated with de novo myelodysplastic syndrome.

     Kreuziger LM, Porcher JC, Ketterling RP, et al. · Leuk Res 2007
     used by KMT2A::SEPTIN9 (MLL-SEPT9 / MLL-MSF), t(11;17)(q23;q25)
197. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17451600
     LEDGF/p75 has increased expression in blasts from chemotherapy-resistant human acute myelogenic leukemia patients and protects leukemia cells from apoptosis in vitro.

     Huang TS, Myklebust LM, et al. · Mol Cancer 2007
     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
198. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17999360
     Type 2 NF1 deletions are highly unusual by virtue of the absence of nonallelic homologous recombination hotspots and an apparent preference for female mitotic recombination

     Steinmann K, Cooper DN, Kluwe L, Kehrer-Sawatzki H, et al. · American Journal of Human Genetics 2007
     used by Meiotic recombination: hundreds of deliberate DNA breaks per cell, made by a topoisomerase relative, at sites chosen by a single zinc-finger protein
199. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17942707
     Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential.

     Wong P, Iwasaki M, Somervaille TCP, So CWE, Cleary ML · Genes & Development 2007
     used by MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed
200. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17927973
     Menin is required in cranial neural crest for palatogenesis and perinatal viability.

     Engleka KA, Wu M, Zhang M, Antonucci NB, Epstein JA · Developmental Biology 2007
     used by Menin is required in neural crest for the palate to close - and both menin inhibitors cause cleft palate in animals
201. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17643375
     Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme.

     Jeronimo C, Forget D, Bouchard A, Li Q, Chua G, Poitras C, Therien C, Bergeron D, Bourassa S, Greenblatt J, Chabot B, Poirier GG, et al · Mol Cell 2007
     used by MEPCE - absent from this graph until now, and a deeper pan-dependency than BRD4
202. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17287850
     Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data.

     van der Velden VH, Cazzaniga G, Schrauder A, et al. · Leukemia 2007
     used by 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, What MRD-negative actually means: a quantitative range, a laboratory judgement, and three incompatible definitions
203. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17268512
     Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement.

     Jansen MW, Corral L, van der Velden VH, et al. · Leukemia 2007
     used by MRD by Ig/TCR rearrangement: the standard in ALL, and the assay infant KMT2A-rearranged disease strains hardest, 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, The pro-B arrest state — what a KMT2A::AFF1 blast is actually doing while it sits there
204. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17699751
     Recruitment of factors linking transcription and processing of pre-rRNA to NOR chromatin is UBF-dependent and occurs independent of transcription in human cells.

     Prieto JL, McStay B · Genes Dev 2007
     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
205. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17879352
     Crystal structure of human nucleophosmin-core reveals plasticity of the pentamer-pentamer interface

     Lee HH, Kim HS, Kang JY, Lee BI, et al. · Proteins 69(3):672-8 2007
     used by NPM1 (nucleophosmin) domain architecture
206. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17545593
     Retroviral insertional mutagenesis identifies genes that collaborate with NUP98-HOXD13 during leukemic transformation

     Slape C, et al. · Cancer Research 67(11):5148-5155 2007
     used by NUP98::HOXD13, t(2;11)(q31;p15) — the myelodysplasia fusion, and a warning against targeting p53
207. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17353269
     Interdependence of Pes1, Bop1, and WDR12 controls nucleolar localization and assembly of the PeBoW complex required for maturation of the 60S ribosomal subunit.

     Rohrmoser M, et al. · Mol Cell Biol 2007
     used by PES1 / pescadillo (O00541) - the missing PeBoW subunit of this graph's nucleolar block, pan-essential in 96.9% of DepMap lines, and the one myeloid experiment on it shows proliferation WITHOUT a differentiation block
208. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17712046
     The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia.

     Catalano A, Dawson MA, Somana K, Opat S, Schwarer A, Campbell LJ, Iland H · Blood 2007
     used by PRKAR1A (P10644) - a PKA regulatory subunit in the pan-MLL-fusion core with no catalytic subunit anywhere in the network, and a fusion oncogene in variant APL
209. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17436247
     Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway.

     Hart CE, Race V, Achouri Y, et al., Van Schaftingen E · Am J Hum Genet 2007
     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
210. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17130830
     Combined effects of the two reciprocal t(4;11) fusion proteins MLL.AF4 and AF4.MLL confer resistance to apoptosis, cell cycling capacity and growth transformation.

     Gaussmann A, Wenger T, Eberle I, et al. · Oncogene 2007
     used by Put both fusion proteins in the same cell and you get something neither produces alone
211. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17923682
     Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes.

     Gregory GD, et al. · Mol Cell Biol 2007
     used by 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
212. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17475909
     The human Shwachman-Diamond syndrome protein, SBDS, associates with ribosomal RNA.

     Ganapathi KA, Austin KM, Lee CS, Dias A et al. · Blood 2007
     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
213. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17803907
     Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7.

     Kremer BE, Adang LA, Macara IG · Cell 2007
     used by SEPTIN2 (septin-2 / NEDD5) — KMT2A fusion partner in t(2;11)(q37;q23)
214. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17575148
     Antagonism of HOX/PBX dimer formation blocks the in vivo proliferation of melanoma

     Morgan R, Pirard PM, Shears L, Sohal J, Pettengell R, Pandha HS · Cancer Research 67:5806-5813 2007
     used by The HOX-PBX interface, and its one peptide: HXR9/HTL001 has been tried in eight tumour types and in KMT2A-rearranged leukaemia exactly once
215. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17184987
     Reconstituted expression of menin in Men1-deficient mouse Leydig tumour cells induces cell cycle arrest and apoptosis

     Hussein N, Casse H, Fontaniere S, Morera AM, Asensio MJ, Bakeli S, Lu JL, Coste I, Di Clemente N, Bertolino P, Zhang CX · European Journal of Cancer 2007
     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
216. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17468513
     Dietary flavonoids induce MLL translocations in primary human CD34+ cells

     Barjesteh van Waalwijk van Doorn-Khosrovani S, Janssen J, Maas LM, et al. · Carcinogenesis 2007
     used by 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
217. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17913746
     The ePHD protein SPBP interacts with TopBP1 and together they co-operate to stimulate Ets1-mediated transcription.

     Sjøttem E, et al. · Nucleic Acids Res 2007
     used by TOPBP1 - a real KMT2A contact that no abstract-level query can see, because it is a control panel in a paper about a different protein
218. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17474113
     Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age.

     Perkins JL, Kunin-Batson AS, Youngren NM, Ness KK, Ulrich KJ, Hansen MJ, Petryk A, Steinberger J, et al. · Pediatric Blood & Cancer 2007
     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
219. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17938197
     UBE2T, the Fanconi anemia core complex, and FANCD2 are recruited independently to chromatin: a basis for the regulation of FANCD2 monoubiquitination.

     Alpi A; Langevin F; Mosedale G; Machida YJ; Dutta A; Patel KJ · Mol Cell Biol 2007
     used by UBE2T — E2; rank 33 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
220. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17290220
     The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2.

     Stevenson LF, Sparks A, Allende-Vega N, Xirodimas DP, Lane DP, Saville MK · The EMBO Journal 2007
     used by USP2 (ubiquitin carboxyl-terminal hydrolase 2) - the ninth commonest KMT2A partner and the only one that is a deubiquitinase
221. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17711858
     The MIT domain of UBPY constitutes a CHMP binding and endosomal localization signal required for efficient epidermal growth factor receptor degradation.

     Row PE, Liu H, Hayes S, Welchman R, Charalabous P, Hofmann K, Clague MJ, Sanderson CM, Urbé S · J Biol Chem 2007
     used by USP8 (UBPY) - the second deubiquitinase KMT2A partner, three patients, same UCH logic
222. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 17361217
     The impact of translocations and gene fusions on cancer causation

     Mitelman F, Johansson B, Mertens F · Nature Reviews Cancer 2007
     used by What is a fusion gene?
223. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16980622
     Disruption of Ledgf/Psip1 results in perinatal mortality and homeotic skeletal transformations.

     Sutherland HG, Newton K, et al. · Mol Cell Biol 2006
     used by "Dispensable for haematopoiesis" is a summary of a real phenotype: halved white counts, perturbed HSC and progenitor numbers, and failing serial replating
224. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
     Interfant-06 treatment protocol for infants under 1 year of age with acute lymphoblastic leukaemia - International collaborative treatment protocol, SKION version 01 (April 2006): chapter 5 chemotherapy schedule and chapter 7 modification for toxicity

     Interfant-06 study group / SKION (Stichting Kinderoncologie Nederland, Dutch Childhood Oncology Group) · Interfant-06 study protocol document (90 pp.) 2006
     used by 6-Mercaptopurine - two years of a nightly tablet whose lethal dose is a genotype, given as a liquid to a baby who cannot swallow it and must not have it with milk, 6-Thioguanine - the drug a 1,498-child randomised trial removed from maintenance and left in intensification, which is exactly where Interfant-06 uses it, Anthracycline cardiotoxicity: the heart an infant keeps for sixty years, 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, 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, Cyclophosphamide - where the KMT2A literature reports two different activated oxazaphosphorines and only one of them is this drug's metabolite, 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, Doxorubicin - named in twenty entries of this graph, cuts the KMT2A breakpoint where etoposide does, and appears nowhere in Interfant-06, 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, 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, Infants are not small children - four maturing organ systems, three conditioning drugs, and a protocol that treats the first year of life as one category, 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, Methotrexate - 5 g/m2 through kidneys that are still maturing, and the one backbone drug the canonical infant sensitivity study never tested, 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, 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, Pegaspargase - the same enzyme wearing a polymer, dosed in units that are not the other product's units, and now dosed to a level in every group except infants, Prednisolone - the active steroid, the drug every resistance experiment in this disease actually used, and the one given into the spinal fluid, Prednisone - the prophase drug, the prognostic factor, and a prodrug that has never itself been tested on a KMT2A-rearranged blast, The Interfant-06 backbone, phase by phase: what the protocol every infant reference in this graph points at actually does, Thiotepa - the third agent that reaches the central nervous system completely, and whose alkylating metabolites are excreted through the skin into a nappy, 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, 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, Weight or surface area - the Interfant-06 conditioning week uses both units in eight days, and the one measured correction in the literature went the wrong way, Who gets transplanted in infant KMT2A-rearranged ALL, and whether it helps - four criteria, and a literature that points both ways
225. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17046466
     Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial.

     Vora A, Mitchell CD, Lennard L, Eden TO, Kinsey SE, Lilleyman J, et al. · Lancet 2006
     used by 6-Thioguanine - the drug a 1,498-child randomised trial removed from maintenance and left in intensification, which is exactly where Interfant-06 uses it
226. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17015055
     The thiopurine methyltransferase genetic polymorphism is associated with thioguanine-related veno-occlusive disease of the liver in children with acute lymphoblastic leukemia.

     Lennard L, Richards S, Cartwright CS, Mitchell C, Lilleyman JS, Vora A · Clin Pharmacol Ther 2006
     used by 6-Thioguanine - the drug a 1,498-child randomised trial removed from maintenance and left in intensification, which is exactly where Interfant-06 uses it
227. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16990798
     Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase.

     Allen MD, Grummitt CG, Hilcenko C, et al. · EMBO J 2006
     used by A published Kd is a property of five experimental choices, and this beat measured how much each one is worth, 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, 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
228. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16921363
     Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L.

     Okada Y, et al. · Nat Cell Biol 2006
     used by A ten-residue export signal is the 5' partner's whole contribution - and the field disagrees about which direction it pushes, CALM-AF10 is predominantly cytoplasmic in transfected non-haematopoietic cells - and NUCLEAR in leukaemia cells (title corrected 2026-09-21; the five systems are five instances of one design), CALM-AF10 reaches DOT1L through exactly the same OM-LZ interface as KMT2A::MLLT10 - the recruitment transfers, the addressing does not, 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, KMT2A::MLLT10 (MLL-AF10), t(10;11)(p12;q23), PICALM::MLLT10 (CALM-AF10), t(10;11)(p13;q14) - the DOT1L-dependent HOXA fusion that contains no KMT2A, The focal half: H3K79 hypermethylation at the HOXA cluster and MEIS1 - but which cluster member differs between CALM-AF10 and MLL-AF10
229. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16690369
     Menin localizes to chromatin through an ATR-CHK1 mediated pathway after UV-induced DNA damage.

     Farley SM, Chen G, Guo S, Wang M, A J, Lee F, Lee F, Sawicki M · J Surg Res 2006
     used by ATR - the replication-stress kinase with the best preclinical case in this disease and the best published reason not to inhibit it, CHEK1 (CHK1) - the node where this graph's chidamide synergy actually lands, and the reason that synergy is an HR-impairment argument, Menin has no subnuclear compartment, and nobody has looked - the whole published record is two biochemical fractionations, both DNA-damage papers, and no microscopy at all, TOPBP1 - a real KMT2A contact that no abstract-level query can see, because it is a control panel in a paper about a different protein
230. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16943429
     Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets.

     Gearhart MD; Corcoran CM; Wamstad JA; Bardwell VJ · Mol Cell Biol 2006
     used by BCOR — the other side of the CBX8 conflict, and a target you would be inhibiting in the direction of disease, RYBP - the subunit that makes a variant PRC1 complex catalytically active, named by two entries in this graph and never written
231. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16862118
     Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9

     Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, Levine JE, Wang J, Hahn WC, Gilliland DG, Golub TR, Armstrong SA · Nature 2006
     used by Bone marrow haematopoietic stem cell — the postnatal comparator, and why the same fusion behaves differently here, Granulocyte-monocyte progenitor (GMP) — the committed cell an MLL fusion can turn back into a stem cell, KMT2A::MLLT3 (MLL-AF9), t(9;11)(p21.3;q23.3), Step 6 — The consequence: self-renewal held on, differentiation never fires, The differentiation block — what it actually is, operationally, in KMT2A::AFF1 leukaemia, The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential, The stem-like self-renewal state — a limited stem-cell module grafted onto a committed cell
232. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17174120
     Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches

     Sugiyama T, Kohara H, Noda M, Nagasawa T · Immunity 2006
     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-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, 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 bone-marrow niche — the address a blood stem cell lives at, which 26 entries in this graph invoke and none had defined, The perivascular and sinusoidal niche — where the functional evidence actually sits, and where the marrow is genuinely hypoxic
233. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16556894
     Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group.

     Hilden JM, Dinndorf PA, et al. · Blood 2006
     used by CCG 1953 (n=115 infants): the first trial to genotype every infant found the partner does not predict outcome, Interfant-99 and Interfant-06: what they report about partners, and what they do not, 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
234. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16582912
     A unique function for cyclin D3 in early B cell development.

     Cooper AB, Sawai CM, Sicinska E, Powers SE, Sicinski P, Clark MR, Aifantis I · Nat Immunol 2006
     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
235. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16721827
     CDC2L5, a Cdk-like kinase with RS domain, interacts with the ASF/SF2-associated protein p32 and affects splicing in vivo.

     Even Y, Durieux S, Escande ML, Lozano JC, Peaucellier G, Weil D, et al. · J Cell Biochem 2006
     used by CDK13 - rank 171 of 17,728, equally deep in both lineage halves, and essentially unstudied in leukaemia
236. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16954369
     Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice.

     Oguro H, Iwama A, Morita Y, Kamijo T, van Lohuizen M, Nakauchi H · J Exp Med 2006
     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
237. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17030982
     Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR.

     Dellaire G, Ching RW, Ahmed K, Jalali F, Tse KC, Bristow RG, Bazett-Jones DP · J Cell Biol 2006
     used by CHEK2 (CHK2) - named in every combination mechanism here and measured on its own in none of them
238. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16400328
     Role of genomic instability and p53 in AID-induced c-myc-Igh translocations

     Ramiro AR, Jankovic M, Callen E, Nussenzweig A, Nussenzweig MC, et al. · Nature 2006
     used by Class switch recombination: a B cell deliberately mutates and cuts its own antibody locus, and the same enzyme causes MYC-IgH translocations, Is fusion intended in biology sometimes? Yes, and the answer has a strategic edge
239. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16838277
     Human MICL (CLEC12A) is differentially glycosylated and is down-regulated following cellular activation.

     Marshall AS, Willment JA, Pyz E, Dennehy KM, Reid DM, Dri P, Gordon S, Wong SY, Brown GD · Eur J Immunol 2006
     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
240. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16482207
     The Bcr-Abl mutations T315I and Y253H do not confer a growth advantage in the absence of imatinib

     Miething C, Feihl S, Mugler C, et al. · Leukemia 2006
     used by Competitive release and adaptive therapy — what ecology says happens when you remove the dominant species, Experiment: does a MEN1 resistance mutant pay a price when the drug is not there? The competition assay nobody has run, Hypothesis: adaptive scheduling of menin inhibitors will fail, because MEN1 resistance mutations probably cost the cell nothing, Hypothesis: menin-inhibitor effect is hysteretic — the program collapses faster than it recovers — so intermittent dosing can hold efficacy at much lower cumulative exposure
241. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17146554
     Cytosine arabinoside-metabolizing enzyme genes are underexpressed in children with MLL gene-rearranged acute lymphoblastic leukemia.

     Mata JF, Scrideli CA, Queiroz RP, Mori BO, Emerenciano M, Pombo-de-Oliveira MS, et al. · Braz J Med Biol Res 2006
     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
242. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17066095
     Resistance of infant leukemia with MLL rearrangement to tumor necrosis factor-related apoptosis-inducing ligand: a possible mechanism for poor sensitivity to antitumor immunity.

     Inukai T, Zhang X, Goto M, Hirose K, Uno K, Akahane K, Nemoto A, Goi K, et al. · Leukemia 2006
     used by Does menin inhibition have any MHC class II headroom to work with in B-precursor infant ALL? A flow cytometry experiment on samples that already exist, 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, Menin inhibition restores graft-versus-leukaemia only where MHC class II is limiting - so the post-transplant maintenance rationale may hold in myeloid disease and fail in B-precursor infant ALL, 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
243. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16636056
     Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCalpha in an aldosterone-sensitive manner.

     Zhang W, Xia X, Reisenauer MR, Hemenway CS, Kone BC · J Biol Chem 2006
     used by DOT1L's localization record is a mouse kidney paper wearing a human label - and the one image of it in a leukaemia cell is a supporting figure a title search cannot see
244. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 16850183
     Cloning and characterization of the human gene DERP6, which activates transcriptional activities of p53.

     Yuan J, Tang W, et al. · Mol Biol Rep 2006
     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
245. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.journal-articlePMID 16651450
     Menin links estrogen receptor activation to histone H3K4 trimethylation

     Dreijerink KM, Mulder KW, Winkler GS, Höppener JW, Lips CJ, Timmers HT · Cancer Research 2006
     used by ESR1 / estrogen receptor alpha - menin's best-documented non-leukaemic partner, and the only one a menin inhibitor is being given to patients to disrupt on purpose
246. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16493009
     Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01

     Loh ML, Goldwasser MA, Silverman LB, Poon WM, Vattikuti S, Cardoso A, Neuberg DS, Shannon KM, Sallan SE, Gilliland DG · Blood 2006
     used by ETV6::RUNX1 (TEL-AML1), t(12;21)(p13;q22)
247. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16875930
     Establishment of a myeloid leukemia cell line, TRL-01, with MLL-ENL fusion gene.

     Ninomiya M, Abe A, Yokozawa T, Ozeki K, et al. · Cancer Genet Cytogenet 2006
     used by Every human t(11;19) KMT2A::MLLT1 cell line, with accessions fetched and read back - and not one of them is known to be reciprocal-negative
248. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16473276
     Forced retinoic acid receptor alpha homodimers prime mice for APL-like leukemia

     Sternsdorf T, Phan VT, Maunakea ML, et al. · Cancer Cell 2006
     used by Experiment (proposed) — cross-family interface point-mutant panel: is the obligate interface real in each fusion?, Hypothesis — forced-oligomerisation interfaces are the mutation-resistant drug targets the fusion field has been ignoring, Mechanism class 2 — transcription-factor corruption (RUNX1::RUNX1T1, PML::RARA, ETV6::RUNX1, CBFB::MYH11) — a balance, not a pure dominant negative, Why PML::RARA became curable — and what KMT2A::AFF1 does not share with it
249. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16880519
     Kinase domain mutants of Bcr-Abl exhibit altered transformation potency, kinase activity, and substrate utilization, irrespective of sensitivity to imatinib

     Griswold IJ, MacPartlin M, Bumm T, et al. · Molecular and Cellular Biology 2006
     used by Experiment: does a MEN1 resistance mutant pay a price when the drug is not there? The competition assay nobody has run, Hypothesis: adaptive scheduling of menin inhibitors will fail, because MEN1 resistance mutations probably cost the cell nothing
250. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16819554
     Foxp1 is an essential transcriptional regulator of B cell development

     Hu H, Wang B, Borde M, Nardone J, Maika S, Allred L, et al. · Nat Immunol 2006
     used by 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
251. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16956839
     MLL/GAS7 fusion in a pediatric case of t(11;17)(q23;p13)-positive precursor B-cell acute lymphoblastic leukemia.

     Panagopoulos I, Lilljebjörn H, Strömbeck B, Hjorth L, Olofsson T, Johansson B · Haematologica 2006
     used by GAS7 — growth-arrest-specific F-BAR protein, the second pillar of the forced-oligomerisation model, KMT2A::GAS7 (MLL-GAS7), t(11;17)(q23;p13) — three patients, and the best mouse model in the partner class
252. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16415179
     p66alpha and p66beta of the Mi-2/NuRD complex mediate MBD2 and histone interaction.

     Brackertz M, Gong Z, Leers J, Renkawitz R · Nucleic Acids Research 2006
     used by GATAD2A / p66-alpha (Q86YP4) - the subunit that bridges NuRD's two modules, the best-ranked NuRD gene in this project's KMT2A-selectivity scan, and present in the pan-fusion interactome under MLL-AF9 but NOT the index fusion, GATAD2B / p66-beta (Q8WXI9) - the NuRD scaffold with the broadest presence in the pan-MLL-fusion interactome, five of seven baits and still not the index fusion, and a haploinsufficiency syndrome that caps any therapeutic idea, No histone-mark readout has ever been measured after perturbing ANY NuRD or Sin3 subunit in a KMT2A-rearranged cell - the two complexes whose entire job is acetylation have zero acetylation data in this disease, The NuRD complex - two separable modules, three paralogue choices that change what it does, and a graph that carried its ATPase and its shared core but never the scaffolds that make it NuRD
253. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16469925
     Histone H4-K16 acetylation controls chromatin structure and protein interactions.

     Shogren-Knaak M; Ishii H; Sun JM; Pazin MJ; Davie JR; Peterson CL · Science 2006
     used by H4K16ac - the one mark rule 80 actually rescued in this beat: elevated at MLL-AF9 targets in a supplementary figure, and the reason MLL1's own enzyme turns out to be dispensable
254. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 17190600
     Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair.

     Botuyan MV, et al. · Cell 2006
     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
255. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16757688
     Leukosialin (CD43) defines hematopoietic progenitors in human embryonic stem cell differentiation cultures

     Vodyanik MA, Thomson JA, Slukvin II · Blood 2006
     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
256. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16728974
     ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression.

     Shi X, Hong T, Walter KL, Ewalt M, Michishita E, Hung T, Carney D, Pena P, Lan F, Kaadige MR, Lacoste N, Cayrou C, Davrazou F, Saha A, Cairns BR, Ayer DE, Kutateladze TG, Shi Y, Cote J, Chua KF, Gozani O · Nature 2006
     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
257. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16397222
     Consistent rearrangement of chromosomal band 6p21 with generation of fusion genes JAZF1/PHF1 and EPC1/PHF1 in endometrial stromal sarcoma

     Micci F, Panagopoulos I, Bjerkehagen B, Heim S · Cancer Res 2006
     used by 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, PHF1 (PCL1) - the PRC2 accessory subunit whose Tudor domain reads H3K36me3, and the 3' acceptor shared by three different NuA4-donor fusions in two different tumour types
258. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 17047066
     Bromodomain and histone acetyltransferase domain specificities control mixed lineage leukemia phenotype.

     Santillan DA, Theisler CM, Ryan AS, Popovic R, Stuart T, Zhou MM, et al. · Cancer Research 66(20):10032-10039 2006
     used by KAT2B / PCAF - named in an existing entry's own id and never written, and the only acetyltransferase in this graph whose substrate is a fusion partner protein
259. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16603238
     Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases

     Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M, Shi Y · Cell 2006
     used by KDM4B (JMJD2B) - the weakest of the four H3K9me3 demethylases, one of the two erasers knocked down in the only KDM4-perturbation arm in any archive that touches this mark
260. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16510874
     The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes.

     Sierra J, Yoshida T, Joazeiro CA, Jones KA · Genes & Development 2006
     used by KMT2A::AFF1–LEF1 is one AP-MS row (p 0.0261, 10|8 spectra) in a Jurkat T-ALL host, where LEF1 is a resident lineage factor; it is the only one of the six AF4-specific candidates with non-zero negative-control signal, and no Wnt co-factor was co-recovered — declined, LEF1 — the Wnt/β-catenin DNA-binding factor of the T-lineage, named as an MLL-AF4-specific interactor in a T-ALL cell line and with essentially no B-lineage or KMT2A literature
261. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16826222
     Establishment of a new human acute monocytic leukemia cell line TZ-1 with t(1;11)(p32;q23) and fusion gene MLL-EPS15.

     Sagawa M, Shimizu T, Shimizu T, Awaya N, Mitsuhashi T, Ikeda Y, et al. · Leukemia 2006
     used by KMT2A::EPS15 (MLL-AF1p), t(1;11)(p32;q23) — the infant-ALL cytoplasmic partner
262. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16897742
     Molecular dissection of t(11;17) in acute myeloid leukemia reveals a variety of gene fusions with heterogeneous fusion transcripts and multiple splice variants.

     Strehl S, König M, Meyer C, Schneider B, Harbott J, Jäger U, et al. · Genes Chromosomes Cancer 2006
     used by KMT2A::MLLT6 (MLL-AF17), t(11;17)(q23;q12-q21) — the bridge case: a leucine zipper on a DOT1L-complex subunit, KMT2A::SEPTIN9 (MLL-SEPT9 / MLL-MSF), t(11;17)(q23;q25)
263. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16682951
     SEPT2 is a new fusion partner of MLL in acute myeloid leukemia with t(2;11)(q37;q23).

     Cerveira N, Correia C, Bizarro S, et al. · Oncogene 2006
     used by KMT2A::SEPTIN2 (MLL-SEPT2), t(2;11)(q37;q23) — the therapy-related septin
264. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17000757
     Nuclear localization signal and protein context both mediate importin alpha specificity of nuclear import substrates.

     Friedrich B, Quensel C, Sommer T, Hartmann E, Kohler M · Mol Cell Biol 2006
     used by KPNA2 / importin-alpha-1 (P52292) - the classical NLS receptor in the pan-MLL-fusion core, and the ONLY karyopherin of any kind in the whole 960-protein network
265. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16951254
     Proteolysis of MLL family proteins is essential for taspase1-orchestrated cell cycle progression

     Takeda S, Chen DY, Westergard TD, Fisher JK, Rubens JA, Sasagawa S, Kan JT, Korsmeyer SJ, Cheng EH, Hsieh JJ · Genes & Development 20(17):2397-2409 2006
     used by 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, TASP1 (taspase1) - the protease that cuts KMT2A, and the timer the fusion escapes
266. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16971064
     Identification and characterization of lin-28 homolog B (LIN28B) in human hepatocellular carcinoma.

     Guo Y, Chen Y, Ito H, Watanabe A, Ge X, Kodama T, Aburatani H · Gene 2006
     used by LIN28B localization - a nucleolar pool that sequesters pri-let-7, a predominantly cytoplasmic steady state with cell-cycle-dependent nuclear entry, and NO measurement in any haematopoietic cell
267. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16981007
     Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations

     Dorrance AM, Liu S, Yuan W, et al. · Journal of Clinical Investigation 116(10):2707-2716 2006
     used by Lost from the KMT2A half: PHD3 and the bromodomain are one cassette, not two modules (aa 1566-1765)
268. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16428440
     MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties.

     Le Guezennec X, Vermeulen M, Brinkman AB, Hoeijmakers WA, Cohen A, Lasonder E, Stunnenberg HG · Molecular and Cellular Biology 2006
     used by MBD3 (O95983) - the methyl-CpG-binding subunit that does NOT bind methylated DNA, and a validated KMT2A::AFF1-selective CRISPR vulnerability that is absent from every column of the pan-fusion interactome, The NuRD complex - two separable modules, three paralogue choices that change what it does, and a graph that carried its ATPase and its shared core but never the scaffolds that make it NuRD
269. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16469876
     Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activation.

     Mamo A, Krosl J, Kroon E, Bijl J, Thompson A, Mayotte N, Girard S, Bijl J, Rosten P, Humphries K, Sauvageau G · Blood 2006
     used by MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed
270. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16449969
     Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression.

     La P, Desmond A, Hou Z, Silva AC, Schnepp RW, Hua X · Oncogene 2006
     used by MEN1 / menin — the adaptor the fusion cannot work without
271. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16607274
     A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technology

     Metzler M, Forster A, Pannell R, et al. · Oncogene 2006
     used by Mll-AF4 mouse genetics — B-lineage tumours, long latency, and never infant pro-B ALL
272. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 17021013
     Coactivator as a target gene specificity determinant for histone H3 lysine 4 methyltransferases.

     Lee S, Lee DK, Dou Y, et al. · Proc Natl Acad Sci U S A 2006
     used by MLL2 and MLL4 each name two different genes, and the ambiguity is in the papers, not in the databases, NCOA6 (ASC-2) - the subunit that gives MLL3 and MLL4 their target genes, and a recorded near-absence in leukaemia
273. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16707593
     Mixed lineage leukemia-rearranged childhood pro-B and CD10-negative pre-B acute lymphoblastic leukemia constitute a distinct clinical entity.

     Attarbaschi A, ..., Dworzak MN · Clin Cancer Res 2006
     used by 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
274. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16767164
     Identification of a region on the outer surface of the CBFbeta-SMMHC myeloid oncoprotein assembly competence domain critical for multimerization

     Zhang L, D'Costa J, Kummalue T, Civin CI, Friedman AD · Oncogene 2006
     used by MYH11 — domain architecture and residue coordinates
275. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16643437
     Lack of expression of the chondroitin sulphate proteoglycan neuron-glial antigen 2 on candidate stem cell populations in paediatric acute myeloid leukaemia/abn(11q23) and acute lymphoblastic leukaemia/t(4;11).

     · Br J Haematol 2006
     used by NG2 is absent from the candidate leukaemia stem-cell populations in t(4;11) ALL and 11q23 AML, so an NG2-directed therapy would debulk the disease and leave the fraction that initiates relapse, 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?
276. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16491129
     The human homologue of the RNA polymerase II-associated factor 1 (hPaf1), localized on the 19q13 amplicon, is associated with tumorigenesis.

     Moniaux N, Nemos C, Schmied BM, Chauhan SC, Deb S, Morikane K, Choudhury A, Vanlith M, Sutherlin M, Sikela JM, Hollingsworth MA, Batra SK · Oncogene 2006
     used by PAF1 is annotated as punctate everywhere in the nucleus EXCEPT the nucleolus - and a 2024 proximity map puts it in the nucleolus
277. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16491119
     The novel CALM interactor CATS influences the subcellular localization of the leukemogenic fusion protein CALM/AF10.

     Archangelo LF, Gläsner J, Krause A, Bohlander SK · Oncogene 2006
     used by PICALM (CALM) - the clathrin-assembly adaptor that is the 5' partner of CALM::AF10
278. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16600869
     Arginine methylation regulates DNA polymerase beta.

     El-Andaloussi N, Valovka T, Toueille M, Steinacher R, Focke F, Gehrig P, Covic M, Hassa PO, Schar P, Hubscher U, Hottiger MO · Molecular Cell 2006
     used by PRMT6 - the enzyme whose mark is MUTUALLY EXCLUSIVE with the MLL complex on the H3 tail, and which shuts HOX genes down by evicting WDR5
279. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16490346
     Adipocytes contain a novel complex similar to the tuberous sclerosis complex.

     Gridley S, Chavez JA, Lane WS et al · Cellular Signalling 2006
     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
280. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16892037
     A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis

     Yan M, Kanbe E, Peterson LF, Boyapati A, Miao Y, Wang Y, Chen IM, Chen Z, Rowley JD, Willman CL, Zhang DE · Nat Med 2006
     used by RUNX1::RUNX1T1 (AML1-ETO), t(8;21)(q22;q22)
281. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     PDB entries 1H9D (AML1/CBF-beta/DNA complex, 'DNA-Induced Molecular Clamp'), 1IO4 (Runt-CBFbeta heterodimer with C/EBPbeta on the CSF1R promoter), 1WQ6 ('The tetramer structure of the Nervy homology two domain, NHR2, is critical for AML1/ETO's activity') and 2ODD ('Solution structure of the MYND domain from AML1-ETO complexed with SMRT')

     RCSB Protein Data Bank · RCSB PDB 2006
     used by RUNX1::RUNX1T1 (AML1-ETO), t(8;21)(q22;q22)
282. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16820529
     SAP30L interacts with members of the Sin3A corepressor complex and targets Sin3A to the nucleolus.

     Viiri KM, Korkeamaki H, Kukkonen MK, Nieminen LK, Lindfors K, Peterson P, Maki M, Kainulainen H, Lohi O · Nucleic Acids Research 2006
     used by SIN3A (Q96ST3) - the scaffold of the OTHER HDAC1/2 corepressor complex, a 5' fusion partner in infant B-ALL and in myelodysplasia, and present in three MLL-fusion AP-MS columns but not the index fusion's
283. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16724116
     HIC1 attenuates Wnt signaling by recruitment of TCF-4 and beta-catenin to the nuclear bodies.

     · EMBO J 2006
     used by TCF7L2 - the protein IntAct's 'DOT1L-TCF4' row is actually about, and the Wnt effector that DOT1L and AF10 coactivate
284. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use

     European Parliament and Council of the European Union · Official Journal of the European Union, L 378/1 2006
     used by The EU paediatric investigation plan: an obligation, not an incentive - and the deferral is the loophole
285. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16551973
     A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy.

     Chen W, Li Q, Hudson WA, et al. · Blood 2006
     used by The experiment nobody has done: an epitope tag knocked into the endogenous KMT2A fusion allele in a patient-derived line
286. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16253272
     Structural basis for cooperative transcription factor binding to the CBP coactivator.

     De Guzman RN, Goto NK, Dyson HJ, Wright PE · J Mol Biol 2006
     used by The KMT2A transactivation domain on the CBP KIX domain: a cooperative allosteric site at 2842-2858, solved three times, and thrown away by every breakpoint
287. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16572268
     Common chromatin structures at breakpoint cluster regions may lead to chromosomal translocations found in chronic and acute leukemias

     Strick R, Zhang Y, Emmanuel N, Strissel PL · Human genetics 2006
     used by The other half of the break: what is actually known about the AFF1 breakpoint region, and the negative-control gene nobody cites
288. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16377807
     MLL rearrangements are induced by low doses of etoposide in human fetal hematopoietic stem cells

     Moneypenny CG, Shao J, Song Y, Gallagher EP · Carcinogenesis 2006
     used by 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
289. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16940357
     Testing gene function early in the B cell lineage in mb1-cre mice.

     Hobeika E, Thiemann S, Storch B, Jumaa H, Nielsen PJ, Pelanda R, Reth M · Proc Natl Acad Sci U S A 2006
     used by The unnamed Cre is Mb1-Cre, which acts at the pro-B stage: the one resolution in this beat that lands on the right cell
290. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16433901
     Simultaneous localization of MLL, AF4 and ENL genes in interphase nuclei by 3D-FISH: MLL translocation revisited

     Gue M, Sun JS, Boudier T · BMC Cancer 2006
     used by 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)
291. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16217841
     Dichotomizing continuous predictors in multiple regression: a bad idea.

     Royston P, Altman DG, Sauerbrei W · Stat Med 2006
     used by WBC 300: a stratification convenience, not a biological threshold - and the evidence says so four different ways
292. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16921038
     Comparison of long-term neurocognitive outcomes in young children with acute lymphoblastic leukemia treated with cranial radiation or high-dose or very high-dose intravenous methotrexate

     Spiegler BJ, Kennedy K, Maze R, Greenberg ML, Weitzman S, Hitzler JK, Nathan PC · Journal of Clinical Oncology 2006
     used by What the treated brain looks like later: neurocognitive late effects after CNS-directed therapy in infancy
293. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16549878
     A tripartite DNA-binding element, comprised of the nuclear localization signal and two AT-hook motifs, mediates the association of LEDGF/p75 with chromatin in vivo.

     Turlure F, Maertens G, Rahman S, Cherepanov P, Engelman A · Nucleic Acids Res 2006
     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
294. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15761502
     Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis

     Ono R, et al. · The Journal of clinical investigation 2005
     used by A partner's 'normal' compartment is usually read off a different tissue, and for at least two KMT2A partners that reading is wrong in blood cells, Cytoplasmic localisation in KMT2A fusions: the SEPTIN case has an image, the GPHN case has none, and neither partner wins the compartment, Experiment — is a KMT2A-septin fusion menin-dependent? The one-plate version, How a cytoskeletal partner reaches chromatin at all — the KMT2A N-terminus drags it in, and the traffic runs both ways, Hypothesis — the elongation hijack is how one partner class satisfies a more general requirement, and the general requirement is what should be drugged, Hypothesis: where a KMT2A fusion sits in the nucleus is set entirely by retained KMT2A modules, and no partner changes the compartment - so every published 'the fusion is here' result is a wild-type KMT2A result, KMT2A::SEPTIN11 (MLL-SEPT11) — the fusion that cytogenetically impersonates t(4;11), KMT2A::SEPTIN6 (MLL-SEPT6), t(X;11)(q24;q23) and its cryptic insertion variants, SEPTIN6 (septin-6) — cytoskeletal GTPase, KMT2A fusion partner in t(X;11)(q24;q23), SEPTIN9 (septin-9 / MSF) — cytoskeletal GTPase, KMT2A fusion partner in t(11;17)(q23;q25), What is actually conserved across KMT2A partner classes — forced self-association, with two documented exceptions that break the rule
295. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15774615
     The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy

     Whitman SP, Liu S, Vukosavljevic T, Rush LJ, Yu L, Liu C, Klisovic MI, Maharry K, Guimond M, Strout MP, Becknell B, Dorrance A, Klisovic RB, Plass C, Bloomfield CD, Marcucci G, Caligiuri MA · Blood 2005
     used by A three-question triage to detect subtraction mechanisms, applied to every KMT2A partner in the graph, 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, KMT2A partial tandem duplication: an addition that only works once the normal copy has been switched off — 'recessive gain-of-function', Subtraction is a partner class, not a curiosity — and the class is defined by compartment, not by sequence
296. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16046533
     Targeting MLL-AF4 with short interfering RNAs inhibits clonogenicity and engraftment of t(4;11)-positive human leukemic cells.

     Thomas M, Gessner A, Vornlocher HP, et al. · Blood 2005
     used by Anti-AFF1 antibodies: attributable on a gel, not attributable in a microscope, and the classic localisation result shows exactly why, 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, Correcting the fusion with genome editing: verdict NOT FEASIBLE for infant leukaemia, though intron-targeted disruption is a real published strategy, Experiment: long-hold degron depletion of endogenous KMT2A::AFF1, to ask whether the leukaemic program recovers without the fusion, Hypothesis: KMT2A::AFF1 is continuously required, not a hit-and-run initiator whose job is done once the epigenome is set, RNA-targeting the fusion transcript: verdict THE LEAST HOPELESS of the three fusion-level routes, blocked by delivery rather than by biology
297. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16193084
     Cleavage of the MLL gene by activators of apoptosis is independent of topoisomerase II activity

     Betti CJ, Villalobos MJ, Jiang Q, et al. · Leukemia 2005
     used by Apoptotic nucleases cut KMT2A, and cells that survive the attempt can carry a translocation, The KMT2A breakpoint cluster region: an 8.3 kb stretch built to break, Topoisomerase II cleavage and TOP2 poisons as a source of KMT2A breaks
298. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 15899874
     5-Aza-deoxycytidine induces selective degradation of DNA methyltransferase 1 by a proteasomal pathway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal.

     Ghoshal K, Datta J, Majumder S, et al. · Mol Cell Biol 2005
     used by Azacitidine - the one hypomethylating agent actually given to infants with KMT2A-rearranged ALL: safe, demonstrably demethylating, and it did not change survival, Decitabine - degrades DNMT1, and in ALL cells it degrades KMT2A too: the hypomethylating agent with two mechanisms and a menin-inhibitor combination already in the clinic, Decitabine degrades DNMT1 - and in ALL cells the same treatment lowers KMT2A protein, with the shared CXXC-family DNA-binding module offered as the reason
299. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16314526
     Association of BMI1 with polycomb bodies is dynamic and requires PRC2/EZH2 and the maintenance DNA methyltransferase DNMT1.

     Hernández-Muñoz I; Taghavi P; Kuijl C; Neefjes J; van Lohuizen M · Mol Cell Biol 2005
     used by BMI1 - the self-renewal gene that KMT2A fusions can do without, because HOXA9 covers for it at the same locus, EED - the PRC2 subunit this disease actually needs, with drugs in the clinic and zero leukaemia studies
300. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16239140
     The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis.

     Yokoyama A, Somervaille TC, Smith KS, Rozenblatt-Rosen O, Meyerson M, Cleary ML · Cell 2005
     used by Bounded failure: the founding menin-cofactor paper names no fusion, has no PMC record and deposited nothing - and three entries depend on it, Co-dependency scan: what else does a menin-dependent cell need? (run, not planned), Experiment — is a KMT2A-septin fusion menin-dependent? The one-plate version, Hypothesis — the elongation hijack is how one partner class satisfies a more general requirement, and the general requirement is what should be drugged, Menin and LEDGF hold WILD-TYPE KMT2A on chromatin; for the fusion LEDGF is functionally required but positionally dispensable, Menin dependence of a non-elongation KMT2A fusion has never been demonstrated — the counted absence, and what the pivotal trial actually enrolled, Menin dependence of KMT2A::MLLT1: real, repeatedly demonstrated, and always as one lane of a partner panel, Menin dependence of KMT2A::MLLT3: the fusion the co-IP was done on, the largest named partner in the pivotal trial, and still no published response rate, Michael Cleary (Stanford) & Akihiko Yokoyama (National Cancer Center, Tsuruoka) — the groups that discovered the menin requirement itself, Necessary is not explanatory: four different questions that a knockout answers as if they were one, Step 6 — The consequence: self-renewal held on, differentiation never fires, The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential, What this beat searched, read and set aside - including one cell line the accession database has not caught up with, and one query that returns a clean zero
301. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16107895
     CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes.

     Dik WA, et al. · Leukemia 2005
     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), PICALM::MLLT10 (CALM-AF10), t(10;11)(p13;q14) - the DOT1L-dependent HOXA fusion that contains no KMT2A, The cell CALM-AF10 arrests: an early T-precursor in adults and a TCR-positive thymocyte in children - two states, split by age (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, The monocytic confound is worse than recorded: two of the six rearranged lines are one patient, and the four-line control group contains a HOXA-driven fusion and two NPM1c/myelomonocytic lines
302. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15452830
     Differential localization and expression of the Cdk9 42k and 55k isoforms.

     Liu H, Herrmann CH · J Cell Physiol 2005
     used by CDK9 - the kinase the whole SEC story runs through, which this graph held only as half of a two-protein summary entry
303. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15710331
     Lack of PTEN sequesters CHK1 and initiates genetic instability.

     Puc J, Keniry M, Li HS, Pandita TK, Choudhury AD, Memeo L, Mansukhani M, Murty VV, Gaciong Z, Meek SE, Piwnica-Worms H, Hibshoosh H, Parsons R · Cancer Cell 2005
     used by CHEK1 (CHK1) - the node where this graph's chidamide synergy actually lands, and the reason that synergy is an HR-impairment argument
304. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16271724
     An intronic peroxisome proliferator-activated receptor-binding sequence mediates fatty acid induction of the human carnitine palmitoyltransferase 1A.

     Napal L, Marrero PF, Haro D · Journal of Molecular Biology 2005
     used by 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
305. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16135807
     Regulation of NuA4 histone acetyltransferase activity in transcription and DNA repair by phosphorylation of histone H4.

     Utley RT, Lacoste N, Jobin-Robitaille O, et al. · Mol Cell Biol 2005
     used by CSNK2A1 (casein kinase 2 alpha) - the one kinase that turns up three separate times in KMT2A biology
306. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15643076
     Separation of the Saccharomyces cerevisiae Paf1 complex from RNA polymerase II results in changes in its subnuclear localization.

     Porter SE, Penheiter KL, Jaehning JA · Eukaryot Cell 2005
     used by CTR9 — a PAF1C subunit the field assumes is a fusion partner, with no paper that tested it
307. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15813846
     Cellular drug sensitivity in MLL-rearranged childhood acute leukaemia is correlated to partner genes and cell lineage.

     Palle J, Frost BM, Forestier E, Gustafsson G, Nygren P, Hellebostad M, et al. · Br J Haematol 2005
     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, 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, 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
308. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15775988
     TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death.

     Ohoka N, Yoshii S, Hattori T, Onozaki K, et al. · EMBO Journal 2005
     used by DDIT3 / CHOP (P35638) - the cascade's middle node, and the symbol whose two reviewed human records and 16,893-record alias are the worst identifier trap in this beat, TRIB3 / TRB3 (Q96RU7) - a pseudokinase that is the ISR's own brake, falls 3.1 log2 under either inhibitor, and has a published physical link to the MLL complex in the wrong tissue
309. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15670842
     Synergistic action of MLL, a TRX protein with template activating factor-I, a histone chaperone.

     Shimoyama T, Kato K, Miyaji-Yamaguchi M, Nagata K · FEBS Letters 2005
     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, 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 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
310. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16039595
     Histone H2B ubiquitylation controls processive methylation but not monomethylation by Dot1 and Set1.

     Shahbazian MD, Zhang K, Grunstein M · Mol Cell 2005
     used by DOT1L methylates H3K79 non-processively - so the three states are one distribution, not three signals, H3K79me1 - the first methyl group, the one H2B ubiquitination is not needed for, and the state HOX loci fall back to as blood cells mature
311. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15851025
     hDOT1L links histone methylation to leukemogenesis.

     Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield VM, Su L, Xu G, Zhang Y · Cell 2005
     used by DOT1L's localization record is a mouse kidney paper wearing a human label - and the one image of it in a leukaemia cell is a supporting figure a title search cannot see
312. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15626757
     Diagnostic tool for the identification of MLL rearrangements including unknown partner genes

     Meyer C, Schneider B, Reichel M, Angermueller S, Strehl S, Schnittger S, Schoch C, Jansen MWJC, van Dongen JJ, Pieters R, Haas OA, Dingermann T, Klingebiel T, Marschalek R · Proc Natl Acad Sci U S A 102:449-454 2005
     used by Each partner prefers a different KMT2A exon: partner-specific break position in 3,401 patients, Step 5: molecular confirmation and naming the partner
313. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16260736
     Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75.

     Cherepanov P, Ambrosio AL, et al. · Proc Natl Acad Sci U S A 2005
     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, HIV-1 integrase on the LEDGF IBD: the same pocket as KMT2A, a thousandfold tighter, and a published competition that displaces the leukaemic complex at IC50 301 nM
314. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15737618
     The tumor suppressor DAL-1/4.1B modulates protein arginine N-methyltransferase 5 activity in a substrate-specific manner.

     Jiang W, Roemer ME, Newsham IF (3 authors; senior author Newsham IF) · Biochem Biophys Res Commun 2005
     used by EPB41L3 / DAL-1 - a membrane-skeleton tumour suppressor that binds and modulates two arginine methyltransferases, and whose own promoter methylation is a clinical test
315. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15528316
     Therapy-related acute myeloid leukemia-like MLL rearrangements are induced by etoposide in primary human CD34+ cells and remain stable after clonal expansion

     Libura J, Slater DJ, Felix CA, Richardson C · Blood 2005
     used by Experiment: bait the KMT2A breakpoint cluster region and sequence everything it joins to, in a fetal-like human progenitor, 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
316. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16195383
     Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c.

     Karnik SK, Hughes CM, Gu X, Rozenblatt-Rosen O, McLean GW, Xiong Y, Meyerson M, Kim SK · Proc Natl Acad Sci U S A 2005
     used by Experiment: read the endocrine limb and the marrow limb of menin-MLL in the SAME animals at the SAME exposure, 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'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
317. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15650050
     Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair.

     Nakanishi K, Yang YG, Pierce AJ, Taniguchi T, Digweed M, D'Andrea AD, Wang ZQ, Jasin M · Proc Natl Acad Sci U S A 2005
     used by FANCD2 — the FA effector menin binds, and the weakest FA gene in this graph's own selectivity scan
318. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15256425
     The Fanconi anemia core complex associates with chromatin during S phase.

     Mi J, Kupfer GM · Blood 2005;105:759-66 2005
     used by FANCL — FA core complex; rank 26 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
319. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15956279
     Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia

     Stam RW, den Boer ML, Schneider P, Nollau P, Horstmann M, Beverloo HB, van der Voort E, Valsecchi MG, de Lorenzo P, Sallan SE, Armstrong SA, Pieters R · Blood 106(7):2484-90 2005
     used by FLT3 in KMT2A-r leukemia — near-universal overexpression, but activating mutation in only ~3% of infants, FLT3 is the second largest KMT2A-selective dependency and it is HEAVIER in B-lineage than in myeloid cells
320. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15684392
     FOXC1 transcriptional regulatory activity is impaired by PBX1 in a filamin A-mediated manner

     Berry FB, O'Neill MA, Coca-Prados M, Walter MA · Molecular and Cellular Biology 25:1415-1424 2005
     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
321. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15948147
     Human Gas7 isoforms homologous to mouse transcripts differentially induce neurite outgrowth.

     Chao CC, Chang P, Lu HH · J Neurosci Res 2005
     used by GAS7 — growth-arrest-specific F-BAR protein, the second pillar of the forced-oligomerisation model
322. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15637143
     Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia.

     Sanders JE, Im HJ, Hoffmeister PA, Gooley TA, Woolfrey AE, Carpenter PA, Andrews RG, Bryant EM, et al. · Blood 2005
     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, 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, Who gets transplanted in infant KMT2A-rearranged ALL, and whether it helps - four criteria, and a literature that points both ways
323. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16307923
     Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation.

     Zhu B, Zheng Y, Pham AD, Mandal SS, Erdjument-Bromage H, Tempst P, Reinberg D · Mol Cell 2005
     used by H2BK120ub (H2Bub1) — the ubiquitin tag on histone H2B that licenses H3K79 methylation, and the mark this graph was missing, PAF1C couples transcription to H2B ubiquitination - but the RTF1 half of that coupling is yeast-specific and contested in human cells, and PAF1C is one of the few complexes that genuinely binds the retained KMT2A fragment, RNF20 (BRE1A) — the H2B ubiquitin ligase that MLL-rearranged leukaemia needs, and that DepMap says every other cancer line needs just as much, RNF40 (BRE1B) — the obligate partner of RNF20, and the one of the pair with a documented link to differentiation and bivalency resolution, UBE2A (RAD6A) — the E2 for H2B ubiquitination in one primary account, contradicted by another, and with no KMT2A literature at all
324. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16129885
     The nuclear-envelope protein and transcriptional repressor LAP2beta interacts with HDAC3 at the nuclear periphery, and induces histone H4 deacetylation.

     Somech R; Shaklai S; Geller O; Amariglio N; Simon AJ; Rechavi G; Gal-Yam EN · J Cell Sci 2005
     used by HDAC3 - the only HDAC in this disease whose requirement was established genetically rather than by a drug, and the same experiment shows it is not fusion-specific
325. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15994294
     Transcription-dependent association of multiple positive transcription elongation factor units to a HEXIM multimer.

     Dulac C, Michels AA, Fraldi A, Bonnet F, Nguyen VT, Napolitano G, Lania L, Bensaude O · J Biol Chem 2005
     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, HEXIM2 - the paralogue that holds the bound P-TEFb pool constant when HEXIM1 is removed, which is why single-gene experiments on this axis read flat
326. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15713662
     HEXIM2, a HEXIM1-related protein, regulates positive transcription elongation factor b through association with 7SK.

     Byers SA, Price JP, Cooper JJ, Li Q, Price DH · J Biol Chem 2005
     used by HEXIM2 - the paralogue that holds the bound P-TEFb pool constant when HEXIM1 is removed, which is why single-gene experiments on this axis read flat
327. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15713661
     Compensatory contributions of HEXIM1 and HEXIM2 in maintaining the balance of active and inactive positive transcription elongation factor b complexes for control of transcription.

     Yik JH, Chen R, Pezda AC, Zhou Q · J Biol Chem 2005
     used by HEXIM2 - the paralogue that holds the bound P-TEFb pool constant when HEXIM1 is removed, which is why single-gene experiments on this axis read flat, HEXIM2 quantitatively compensates for HEXIM1 loss to hold the 7SK-bound P-TEFb pool constant - which makes single-gene knockdown of either a buffered experiment, and is the reason a HEXIM1-only measurement cannot be read as the brake's strength, How P-TEFb gets out of the reservoir: a dephosphorylation, a dissociation, and a reassembly on whichever scaffold is waiting, The 7SK snRNP - a stable RNA core with a reversibly docked kinase, which is why the reservoir is a switch and not a sink
328. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16314519
     Disruption of Sept6, a fusion partner gene of MLL, does not affect ontogeny, leukemogenesis induced by MLL-SEPT6, or phenotype induced by the loss of Sept4.

     Ono R, Ihara M, Nakajima H, et al. · Mol Cell Biol 2005
     used by How a cytoskeletal partner reaches chromatin at all — the KMT2A N-terminus drags it in, and the traffic runs both ways, KMT2A::SEPTIN6 (MLL-SEPT6), t(X;11)(q24;q23) and its cryptic insertion variants, Non-elongation KMT2A partners considered and not written: what the searches actually returned, partner by partner, SEPTIN11 (septin-11) — KMT2A fusion partner at 4q21, adjacent to AFF1, SEPTIN2 (septin-2 / NEDD5) — KMT2A fusion partner in t(2;11)(q37;q23), SEPTIN5 (septin-5 / CDCrel-1) — KMT2A fusion partner in t(11;22)(q23;q11.2), SEPTIN6 (septin-6) — cytoskeletal GTPase, KMT2A fusion partner in t(X;11)(q24;q23)
329. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15657436
     Eukaryotic translation initiation factor 4E activity is modulated by HOXA9 at multiple levels.

     Topisirovic I, Kentsis A, Perez JM, Guzman ML, Jordan CT, Borden KL · Mol Cell Biol 2005
     used by HOXA9 has its own nuclear bodies, and in monocytic AML they move into the eIF4E body - a subnuclear switch measured in patient marrow and never genotyped
330. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15640349
     Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors.

     Milne TA, Hughes CM, Lloyd R, Yang Z, Rozenblatt-Rosen O, Dou Y, Schnepp RW, Krankel C, Livolsi VA, Gibbs D, Hua X, Roeder RG, Meyerson M, Hess JL · Proc Natl Acad Sci U S A 2005
     used by 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'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
331. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15960975
     Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF.

     Dou Y, Milne TA, Tackett AJ, Smith ER, Fukuda A, Wysocka J, Allis CD, Chait BT, Hess JL, Roeder RG · Cell 2005
     used by KAT8 (MOF) — a genuine KMT2A partner that binds the half of KMT2A the fusion discards, Lost from the KMT2A half: the MOF/KAT8 contact - required in the cell, but not shown to matter to the fusion, Lost from the KMT2A half: the SET domain (aa 3829-3945) - the lost module whose loss demonstrably does not matter, MOF/KAT8 is required by both KMT2A::MLLT3 and NUP98::HOXA9 — which is why it is the wrong kind of convergence
332. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15540222
     Activation of HLXB9 by juxtaposition with MYB via formation of t(6;7)(q23;q36) in an AML-M4 cell line (GDM-1).

     Nagel S, Kaufmann M, Scherr M, Drexler HG, MacLeod RAF · Genes Chromosomes Cancer 2005
     used by 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
333. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15751040
     MLL is fused to EB1 (MAPRE1), which encodes a microtubule-associated protein, in a patient with acute lymphoblastic leukemia.

     Fu JF, Hsu HC, Shih LY · Genes Chromosomes Cancer 2005
     used by KMT2A::MAPRE1 (MLL-EB1) - a coiled-coil dimerisation fusion from pro-B ALL with a mouse model, low leukaemogenic potential, and Ets1 as its effector, MAPRE1 / EB1 (Q15691) - a microtubule plus-end tracking protein that is BOTH a pan-MLL-fusion prey and a genuine KMT2A fusion partner in pro-B ALL
334. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15856011
     The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin.

     Zeisig DT, Bittner CB, Zeisig BB, et al. · Oncogene 2005
     used by KMT2A::MLLT1 engages P-TEFb through one 66-residue surface: the ENL AHD, residues 494-559, and L550E breaks it, Where KMT2A::MLLT1 actually sits: chromatin occupancy is mapped, subnuclear localisation of the endogenous fusion has never been imaged
335. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15897884
     The MYO1F, unconventional myosin type 1F, gene is fused to MLL in infant acute monocytic leukemia with a complex translocation involving chromosomes 7, 11, 19 and 22.

     Taki T, Akiyama M, Saito S, Ono R, Taniwaki M, Kato Y, et al. · Oncogene 2005
     used by KMT2A::MYO1F, t(11;19)(q23;p13.2) — recurrent in infant AML, and never functionally tested, MYO1F — unconventional myosin IF, a KMT2A partner with neither a transactivation domain nor a dimerisation domain
336. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15640245
     Sotos syndrome common deletion is mediated by directly oriented subunits within inverted Sos-REP low-copy repeats

     Kurotaki N, Stankiewicz P, Wakui K, Niikawa N, Lupski JR · Human Molecular Genetics 2005
     used by Meiotic recombination: hundreds of deliberate DNA breaks per cell, made by a topoisomerase relative, at sites chosen by a single zinc-finger protein
337. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16172981
     PBX1 intracellular localization is independent of MEIS1 in epithelial cells of the developing female genital tract.

     Dintilhac A, Bihan R, Guerrier D, Deschamps S, Bougerie H, Watrin T, Bonnec G, Pellerin I · Int J Dev Biol 2005
     used by MEIS1's 'nucleus' is a profile prediction, not a measurement - and a homeodomain-less isoform is cytoplasmic and does the opposite job
338. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15563473
     Menin suppresses osteoblast differentiation by antagonizing the AP-1 factor, JunD.

     Naito J, Kaji H, Sowa H, Hendy GN, Sugimoto T, Chihara K · Journal of Biological Chemistry 2005
     used by Menin builds bone early and blocks it late: two opposite jobs in the same lineage
339. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16091750
     BCL11B functionally associates with the NuRD complex in T lymphocytes to repress targeted promoter.

     Cismasiu VB, Adamo K, Gecewicz J, Duque J, Lin Q, Avram D · Oncogene 2005
     used by MTA2 / MTA1L1 (O94776) - the NuRD scaffold that clamps HDAC1, recruited in T lymphocytes by BCL11B, and absent together with MTA1 and MTA3 from every column of the pan-MLL-fusion interactome
340. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15723053
     c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription.

     Arabi A; Wu S; Ridderstråle K; Bierhoff H; Shiue C; Fatyol K; Fahlén S; Hydbring P; Söderberg O; Grummt I; Larsson LG; Wright AP · Nat Cell Biol 2005
     used by MYC - named in a hundred entries of this graph and, until now, written in none, TRRAP — a 3,859-residue DotCom subunit that every cell needs and no KMT2A cell needs more
341. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15659725
     Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype

     Falini B, Mecucci C, Tiacci E, Alcalay M, et al. · N Engl J Med 352(3):254-66 2005
     used by NPM1 (nucleophosmin) — the nucleolar shuttle whose mutant form binds chromatin with KMT2A and buys the second menin-inhibitor indication
342. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 16079892
     Cell line OCI/AML3 bears exon-12 NPM gene mutation-A and cytoplasmic expression of nucleophosmin

     Quentmeier H, Martelli MP, Dirks WG, Bolli N, et al. · Leukemia 19(10):1760-7 2005
     used by NPM1 (nucleophosmin) — the nucleolar shuttle whose mutant form binds chromatin with KMT2A and buys the second menin-inhibitor indication
343. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15705808
     An acylation cycle regulates localization and activity of palmitoylated Ras isoforms.

     · Science 2005
     used by NRAS - the other RAS, the one whose 0.3% clone came back, and a UniProt record that lists HRAS1 as its own synonym
344. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16355229
     The Rae1-Nup98 complex prevents aneuploidy by inhibiting securin degradation

     Jeganathan KB, Malureanu L, van Deursen JM · Nature 2005
     used by NUP98 - the mobile nucleoporin that leaves the pore to put H3K4me3 on haematopoietic promoters, and the shared 5' donor of seven fusions in this graph
345. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15755899
     NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia

     Lin YW, et al. · Blood 106(1):287-295 2005
     used by NUP98::HOXD13, t(2;11)(q31;p15) — the myelodysplasia fusion, and a warning against targeting p53
346. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16262731
     Effect of clathrin assembly lymphoid myeloid leukemia protein depletion on clathrin coat formation.

     Meyerholz A, Hinrichsen L, Groos S, Esk PC, Brandes G, Ungewickell EJ · Traffic 2005
     used by PICALM (CALM) - the clathrin-assembly adaptor that is the 5' partner of CALM::AF10
347. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15728131
     Derivation of 2 categories of plasmacytoid dendritic cells in murine bone marrow.

     Pelayo R, Hirose J, Huang J, Garrett KP, Delogu A, Busslinger M, Kincade PW · Blood 2005
     used by Pre-pro-B cell (murine Hardy Fraction A) - the stage before pro-B, with germline immunoglobulin genes, and the stage RYBP loss actually removes
348. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15767345
     Maternal diet and infant leukemia: the DNA topoisomerase II inhibitor hypothesis: a report from the children's oncology group

     Spector LG, Xie Y, Robison LL, Heerema NA, Hilden JM, Lange B, et al. · Cancer Epidemiology, Biomarkers & Prevention 2005
     used by Prevention by exposure avoidance: verdict NOT FEASIBLE, and the transplacental-exposure literature is much weaker than its prominence suggests
349. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15494416
     PRMT7, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine.

     Lee JH, Cook JR, Yang ZH, Mirochnitchenko O, et al. · J Biol Chem 2005
     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
350. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16129689
     Interaction of the Epstein-Barr virus mRNA export factor EB2 with human Spen proteins SHARP, OTT1, and a novel member of the family, OTT3, links Spen proteins with splicing regulation and mRNA export.

     Hiriart E, Gruffat H, Buisson M, Mikaelian I, Keppler S, Meresse P, et al. · J Biol Chem 2005
     used by RBM15B — the bridge from the DOT1L mark to the RNA layer: it reads H3K79me2 and steers m6A to start codons
351. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16185711
     Histone H3 lysine 4 mono-methylation does not require ubiquitination of histone H2B.

     · J Mol Biol 2005
     used by RTF1 — the PAF1C subunit the graph was missing, on a complex that does bind the retained KMT2A fragment
352. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15774761
     A mitotic septin scaffold required for Mammalian chromosome congression and segregation.

     Spiliotis ET, Kinoshita M, Nelson WJ · Science 2005
     used by SEPTIN2 (septin-2 / NEDD5) — KMT2A fusion partner in t(2;11)(q37;q23)
353. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15647371
     Human splicing factor SF3a, but not SF1, is essential for pre-mRNA splicing in vivo.

     Tanackovic G, Kramer A · Mol Biol Cell 2005
     used by SF3A3 / SF3a60 (Q12874) - a U2 snRNP splicing subunit in the pan-MLL-fusion core, and the paper's own named example of a NON-selective hit
354. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16024656
     The human PAF complex coordinates transcription with events downstream of RNA synthesis.

     Zhu B, Mandal SS, Pham AD, Zheng Y et al. · Genes Dev 2005
     used by SKIC8 (formerly WDR61) — the last PAF1C subunit, and a gene-symbol trap worth recording
355. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15833859
     BCR-ABL induces the expression of Skp2 through the PI3K pathway to promote p27Kip1 degradation and proliferation of chronic myelogenous leukemia cells.

     Andreu EJ, Lledó E, Poch E, Ivorra C et al. · Cancer Res 2005
     used by SKP2 - the substrate receptor that grips the retained fragment; two nodes in this graph already pointed at it as a free-text string with nothing to point to
356. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16149049
     Subnuclear targeting of Runx1 is required for synergistic activation of the myeloid specific M-CSF receptor promoter by PU.1.

     Li X, Vradii D, Gutierrez S, Lian JB et al. · J Cell Biochem 2005
     used by SPI1 / PU.1 — a myeloid dependency that a KMT2A panel mistakes for its own
357. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     PDB 2A8I: Crystal Structure of human Taspase1

     Khan JA, Dunn BM, Tong L · RCSB Protein Data Bank 2005
     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
358. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15930015
     The Treacher Collins syndrome (TCOF1) gene product is involved in pre-rRNA methylation.

     Gonzales B, Henning D, So RB, Dixon J, Dixon MJ, Valdez BC · Hum Mol Genet 2005
     used by TCOF1 / treacle (Q13428) - the Treacher Collins nucleolar phosphoprotein in the MLL-fusion nucleolar block, the block's only link to rDNA damage signalling through NBS1, and the only member whose loss causes a named human developmental syndrome
359. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 16172399
     Metastasis-associated protein 1 (MTA1) is an essential downstream effector of the c-MYC oncoprotein.

     Zhang XY, DeSalle LM, Patel JH, Capobianco AJ, Yu D, Thomas-Tikhonenko A, et al. · Proc Natl Acad Sci U S A 2005
     used by When MYC falls after a menin inhibitor, there are three mechanisms it could be, and no published experiment separates them
360. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 16061479
     Pc2-mediated sumoylation of Smad-interacting protein 1 attenuates transcriptional repression of E-cadherin.

     · J Biol Chem 2005
     used by ZEB2 — an EMT transcription factor that turns out to be a leukemia dependency and a guardian of lineage fidelity
361. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 14603337
     MLL fusion partners AF4 and AF9 interact at subnuclear foci

     Erfurth F, et al. · Leukemia 2004
     used by 'AF4 bodies' - a named subnuclear compartment that is non-nucleolar and coincident with no known nuclear structure, and the one place a KMT2A fusion has been shown to move a partner, AFF1 / AF4 — the 3' half of the fusion, and a target with almost no structural footing, MLLT3 / AF9 — a famous fusion partner that is not a dependency, and a hub domain that is, Where KMT2A::MLLT3 sits in the nucleus: two papers, both overexpression, both from before 2005 - and the fusion carries no AF9 import signal
362. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 14707170
     An abundance of bidirectional promoters in the human genome

     Trinklein ND, Aldred SF, Hartman SJ, Schroeder DI, Otillar RP, Myers RM · Genome Research 2004
     used by 21.6% of this project's 19,404 promoter windows contain another gene's TSS, so an attribution caveat is corpus-wide and not an IRX2 peculiarity, A promoter window is not a gene: what it means to say a protein 'sits on gene X's switch'
363. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 14712291
     In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype.

     Ramakers-van Woerden NL, Beverloo HB, Veerman AJ, Camitta BM, Loonen AH, van Wering ER, et al. · Leukemia 2004
     used by 6-Mercaptopurine - two years of a nightly tablet whose lethal dose is a genotype, given as a liquid to a baby who cannot swallow it and must not have it with milk, 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, 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, Pegaspargase - the same enzyme wearing a polymer, dosed in units that are not the other product's units, and now dosed to a level in every group except infants, Prednisolone - the active steroid, the drug every resistance experiment in this disease actually used, and the one given into the spinal fluid, Prednisone - the prophase drug, the prognostic factor, and a prodrug that has never itself been tested on a KMT2A-rearranged blast, 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
364. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15214844
     Subcellular localization of EEN/endophilin A2, a fusion partner gene in leukaemia

     Cheung N, et al. · The Biochemical journal 2004
     used by A partner's 'normal' compartment is usually read off a different tissue, and for at least two KMT2A partners that reading is wrong in blood cells, Enumeration for the subnuclear beat: every compartment queried, every count, and the papers that looked on-topic and were not used, How a cytoskeletal partner reaches chromatin at all — the KMT2A N-terminus drags it in, and the traffic runs both ways
365. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15199122
     Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression

     Yokoyama A, Wang Z, ..., Cleary ML · Molecular and Cellular Biology 2004
     used by Absence claims: 93% are unbounded in prose, but the evidence claims are 71% bounded - and the query that tested them was itself broken, AFF1-NPM1 proximity: nucleophosmin is the only bait in any published proximity experiment whose neighbourhood contains AFF1, KMT2A and menin together, ASH2L — the WRAD subunit that has DPY30's essentiality profile and none of its co-dependency signal, ASH2L: the only WRAD subunit ever perturbed in a KMT2A::AFF1 cell, once, weakly, DPY30 — the smallest COMPASS subunit, and the only one that behaves like a selective dependency, DPY30: the founding negative does not cover it, and it has no KMT2A contact to lose, Enumerating the WRAD-versus-KMT2A-fusion literature: what was searched, found, rejected and could not be read, Every IntAct number in this project is drawn through a query that misses half the record - and what it misses is the taspase1 fragments, Experiment: put four residues back - the minimal add-back control the PHD3 result has never had, First systematic enumeration of the KMT2A fusion interactome, and the diff against this graph, HCFC1 (HCF-1) — a founding member of the wild-type KMT2A complex that the fusion cannot bind, HCFC2 — menin's other host cell factor, present in the founding paper by gel filtration and never mentioned again, KMT2A sits in the 14-3-3 proximity neighbourhood, and the YWHAG link reproduces across two independent studies, 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: the four-residue HCF-binding motif (DHNY, aa 1799-1802), Lost from the KMT2A half: the WIN motif and the whole WRAD interface (aa 3762-3767, Arg3765), Menin is the best handle on KMT2A::AFF1 because of where the break falls, not because menin is biologically special, Proximity-labelling map of KMT2A::AFF1 — the experiment nobody has run in twenty years of interactome work, 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, Settle the WRAD question: tagged co-IP plus degron-timed proximity across three fusion classes, The founding WRAD negative was never run on a fusion protein, The graph's universal 'every KMT2A fusion loses the SET domain' is a silent, propagating error class, UTP18 is not a KMT2A partner - it is WDR5, mis-curated into IntAct from the founding paper, and it manufactured the only KMT2A-bait gap in the interactome recount, Verdict on the WRAD contradiction: the graph is right, its citation class is wrong, and its universal is wrong, WDR5 — the partner that is not a partner: it binds the half of KMT2A the fusion throws away, 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, WDR5: an established wild-type KMT2A contact, and no fusion contact ever measured, Wild-type KMT2A is one of the most promiscuously labelled proteins in the proximity record - 25 of 50 baits - and menin is one of the least, at 3
366. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15221006
     Interaction of AF4 wild-type and AF4.MLL fusion protein with SIAH proteins: indication for t(4;11) pathobiology?

     Bursen A, Moritz S, Gaussmann A, Moritz S, Dingermann T, Marschalek R · Oncogene 23:6237-6249 2004
     used by AFF1 / AF4 — domain architecture and residue coordinates, AFF1 as the subtraction control: the refutation is WITHDRAWN - the degron is lost, not retained, AFF1::KMT2A (AF4-MLL), the der(4) product: what it is made of, residue by residue, 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, Hypothesis: what the KMT2A half loses is control of its own abundance, not control of its activity, SIAH1 — the E3 ligase that degrades AFF1, and that the reciprocal AF4::KMT2A fusion escapes, SIAH1/SIAH2: the disposal route that destroys wild-type AF4 and that the reciprocal fusion escapes, SIAH2 — the second AFF1 E3 ligase, reported only alongside SIAH1 and never separated from it, 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
367. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15269783
     The synthetic peptide PFWT disrupts AF4-AF9 protein complexes and induces apoptosis in t(4;11) leukemia cells.

     Srinivasan RS, Nesbit JB, Marrero L, Erfurth F, LaRussa VF, Hemenway CS · Leukemia 2004
     used by AFF1 AF4_int motif to AF9/ENL AHD: the index fusion's only documented elongation interface, and it competes with DOT1L, 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
368. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15459319
     Mediation of Af4 protein function in the cerebellum by Siah proteins

     Oliver PL, Bitoun E, Clark J, Jones EL, Davies KE · Proceedings of the National Academy of Sciences USA 2004
     used by AFF1 as the subtraction control: the refutation is WITHDRAWN - the degron is lost, not retained, 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, 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
369. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15175163
     A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology.

     Sato S, Tomomori-Sato C, Parmely TJ, Florens L, Zybailov B, Swanson SK, Banks CAS, Jin J, Cai Y, Washburn MP, Conaway JW, Conaway RC · Mol Cell 2004
     used by AFF4-MED10: AFF4 is prey in a 2004 Mediator MudPIT purification - a lead with an independent mechanistic reason to be true, and no experiment that tests it, MED19 - the Mediator subunit curated against an engineered MLL-AFF4 fusion protein, and the one REST uses to deliver G9a
370. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 14871897
     Recruitment of the cell cycle checkpoint kinase ATR to chromatin during S-phase.

     Dart DA, Adams KE, Akerman I, Lakin ND · J Biol Chem 2004
     used by ATR - the replication-stress kinase with the best preclinical case in this disease and the best published reason not to inhibit it
371. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15169896
     The TALE homeodomain protein Pbx2 is not essential for development and long-term survival.

     Selleri L, DiMartino J, van Deursen J, et al., Cleary ML · Mol Cell Biol 2004
     used by Blot all three PBX proteins in KMT2A::AFF1 B-lineage cells, then delete them singly and in combination - the family has never been tested together in any human leukaemia line, PBX2 - an AFF4 co-purifying protein in two rounds of one AP-MS atlas, and the PBX paralogue the leukaemia literature explicitly excluded, The PBX requirement in KMT2A-rearranged leukaemia is a family property, and every experiment that shaped this graph's view of it removed one paralogue at a time
372. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15386022
     Role of histone H2A ubiquitination in Polycomb silencing.

     · Nature 2004
     used by BMI1 - the self-renewal gene that KMT2A fusions can do without, because HOXA9 covers for it at the same locus
373. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15509584
     Ring1b-mediated H2A ubiquitination associates with inactive X chromosomes and is involved in initiation of X inactivation.

     · J Biol Chem 2004
     used by BMI1 - the self-renewal gene that KMT2A fusions can do without, because HOXA9 covers for it at the same locus
374. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 14765118
     Structural basis of HP1/PXVXL motif peptide interactions and HP1 localisation to heterochromatin.

     Thiru A, et al. · EMBO J 2004
     used by CBX1 / HP1-beta (P83916, 185 aa) - the HP1 paralogue with the fitness cost and no role in this graph's cascade: DepMap mean -0.349 with 16.6% of 1,257 lines below -0.5, four times deeper than HP1-gamma or HP1-alpha, and zero papers place it anywhere near KMT2A
375. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15358120
     Cyclin D3 interacts with human activating transcription factor 5 and potentiates its transcription activity.

     Liu W, Sun M, Jiang J, Shen X, Sun Q, Liu W, Shen H, Gu J · Biochem Biophys Res Commun 2004
     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
376. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 14627702
     Phosphorylated positive transcription elongation factor b (P-TEFb) is tagged for inhibition through association with 7SK snRNA.

     Chen R, Yang Z, Zhou Q · J Biol Chem 2004
     used by CDK9 - the kinase the whole SEC story runs through, which this graph held only as half of a two-protein summary entry, How P-TEFb gets out of the reservoir: a dephosphorylation, a dissociation, and a reassembly on whichever scaffold is waiting, The 7SK snRNP - a stable RNA core with a reversibly docked kinase, which is why the reservoir is a switch and not a sink
377. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 14718166
     Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis.

     Tagami H, Ray-Gallet D, Almouzni G, et al. · Cell 2004
     used by CHAF1A (CAF-1 p150) - the subunit that reads PCNA and makes histone deposition replication-coupled, and the half of CAF-1 that leukaemia has not looked at, CHAF1B (CAF-1 p60) - the one histone chaperone in this beat with a real leukaemia literature, and a mouse experiment that contradicts DepMap's verdict on its druggability, HIRA - the chaperone that puts new H3.3 into transcribed gene bodies, and therefore the machine that runs this graph's clearance clock, The HUCA complex (HIRA/UBN1/CABIN1/ASF1a) - four proteins, one job: put H3.3 into chromatin without waiting for S phase
378. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15311285
     Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase.

     Krämer A, Mailand N, Lukas C, Syljuasen RG, Wilkinson CJ, Nigg EA, Bartek J, Lukas J · Nat Cell Biol 2004
     used by CHEK1 (CHK1) - the node where this graph's chidamide synergy actually lands, and the reason that synergy is an HR-impairment argument
379. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15315756
     AID is required for c-myc/IgH chromosome translocations in vivo

     Ramiro AR, Jankovic M, Eisenreich T, Honjo T, Nussenzweig A, Nussenzweig MC, et al. · Cell 2004
     used by Class switch recombination: a B cell deliberately mutates and cuts its own antibody locus, and the same enzyme causes MYC-IgH translocations
380. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15548716
     C-type lectin-like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia.

     Bakker AB, van den Oudenrijn S, Bakker AQ, Feller N, van Meijer M, Bia JA, et al. · Cancer Res 2004
     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, Risk: CLEC12A-directed therapy ablates normal granulocytes and disables an inhibitory brake on NET formation - the toxicity is mature-myeloid, not stem-cell
381. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15542854
     Binding to nonmethylated CpG DNA is essential for target recognition, transactivation, and myeloid transformation by an MLL oncoprotein

     Ayton PM, Chen EH, Cleary ML · Molecular and Cellular Biology 24(23):10470-8 2004
     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: a topology-controlled binding survey of the MLL AT-hook region, plus a triple AT-hook alanine mutant in an endogenously tagged fusion, HOXA-high versus HOXA-low KMT2A-rearranged leukemia — the split that breaks the one-mechanism story, Hypothesis: KMT2A::AFF1 does not require phase separation — recruitment biochemistry is sufficient, and the condensate model does not transfer from NUP98/ENL, Hypothesis: the cell-of-origin methylome, not the breakpoint, decides whether a KMT2A::AFF1 leukemia is HOXA-high or HOXA-low, Plain-English: chromatin and epigenetics — the sticky notes on the DNA, and which ones matter here, Step 1 — How the fusion finds its genes: AT-hooks and the CXXC domain reading unmethylated CpG, The clustered PHD fingers (KMT2A aa 1416-1640) are a chromatin-targeting module and the canonical t(4;11) junction removes them by ten residues, The CXXC domain (aa 1147-1195, PDB 2KKF) is a chromatin address, not a compartment address — CpG mutants lose transformation but keep their subnuclear position, The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential, The strongest published case that condensates are load-bearing in KMT2A-fusion leukemia — and it is AKAP95, not AFF1, Where KMT2A and its fusions sit inside the nucleus — SNL1/SNL2, nuclear speckles and the condensate question
382. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 14759373
     CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species.

     Yusufzai TM, Tagami H, Nakatani Y, Felsenfeld G · Mol Cell 2004
     used by 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
383. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 14751928
     The small oligomerization domain of gephyrin converts MLL to an oncogene

     Eguchi M, et al. · Blood 2004
     used by Cytoplasmic localisation in KMT2A fusions: the SEPTIN case has an image, the GPHN case has none, and neither partner wins the compartment, GPHN (gephyrin) — synaptic scaffold and molybdenum-cofactor enzyme, KMT2A fusion partner in t(11;14)(q23;q24), Hypothesis — the elongation hijack is how one partner class satisfies a more general requirement, and the general requirement is what should be drugged, Hypothesis: tubulin/microtubule association is a recurrent, unnamed property of the KMT2A partners whose transforming module has no other assignment, KMT2A::GPHN (MLL-gephyrin), t(11;14)(q23;q24) — the 15-residue counterexample, Reading the same-source counter-evidence: 77 notes adjudicated, and the defect is not the one the metric measures, What is actually conserved across KMT2A partner classes — forced self-association, with two documented exceptions that break the rule
384. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15252119
     Heterochromatin and ND10 are cell-cycle regulated and phosphorylation-dependent alternate nuclear sites of the transcription repressor Daxx and SWI/SNF protein ATRX.

     Ishov AM, Vladimirova OV, Maul GG · J Cell Sci 2004
     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
385. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15334549
     Characterization of genomic breakpoints in MLL and CBP in leukemia patients with t(11;16)

     Zhang Y, Zeleznik-Le N, Emmanuel N, Jayathilaka N, Chen J, Strissel P, Strick R, Li L, Neilly MB, Taki T, Hayashi Y, Kaneko Y, Schlegelberger B, Rowley JD · Genes Chromosomes Cancer 41:257-265 2004
     used by Each partner prefers a different KMT2A exon: partner-specific break position in 3,401 patients
386. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15334060
     DAL-1/4.1B tumor suppressor interacts with protein arginine N-methyltransferase 3 (PRMT3) and inhibits its ability to methylate substrates in vitro and in vivo.

     Singh V, Miranda TB, Jiang W, et al. (10 authors; senior author Newsham IF) · Oncogene 2004
     used by EPB41L3 / DAL-1 - a membrane-skeleton tumour suppressor that binds and modulates two arginine methyltransferases, and whose own promoter methylation is a clinical test, 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
387. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 14670924
     FLT3 mutations in childhood acute lymphoblastic leukemia

     Armstrong SA, Mabon ME, Silverman LB, Li A, Gribben JG, Fox EA, Sallan SE, Korsmeyer SJ · Blood 103(9):3544-6 2004
     used by FLT3 in KMT2A-r leukemia — near-universal overexpression, but activating mutation in only ~3% of infants
388. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 15492844
     Human FOX gene family (Review)

     Katoh M, Katoh M · International Journal of Oncology 25:1495-1500 2004
     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
389. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15070702
     Leukemic transformation of hematopoietic progenitors by MLL-GAS7 in the absence of Hoxa7 or Hoxa9.

     So CW, Karsunky H, Wong P, Weissman IL, Cleary ML · Blood 2004
     used by GAS7 — growth-arrest-specific F-BAR protein, the second pillar of the forced-oligomerisation model, KMT2A::GAS7 (MLL-GAS7), t(11;17)(q23;p13) — three patients, and the best mouse model in the partner class
390. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15356041
     Factors that affect final height and change in height standard deviation scores in survivors of childhood cancer treated with growth hormone: a report from the Childhood Cancer Survivor Study

     Brownstein CM, Mertens AC, Mitby PA, Stovall M, Qin J, Heller G, Robison LL, Sklar CA · The Journal of Clinical Endocrinology and Metabolism 2004
     used by Growth and endocrine consequences of being treated for leukemia as a baby
391. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15345777
     Human PAD4 regulates histone arginine methylation levels via demethylimination.

     Wang Y, Wysocka J, Sayegh J, Lee YH, et al. · Science 2004
     used by 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, 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
392. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15339660
     Histone deimination antagonizes arginine methylation.

     Cuthbert GL, Daujat S, Snowden AW, Erdjument-Bromage H, et al. · Cell 2004
     used by 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, H4R3me2s - the repressive symmetric arginine mark that recruits DNMT3A, blocks a KMT2 enzyme's own PHD module, and is the ONLY arginine mark ever measured in a KMT2A-fusion system
393. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15254242
     Thrombopoietin induces HOXA9 nuclear transport in immature hematopoietic cells: potential mechanism by which the hormone favorably affects hematopoietic stem cells.

     Kirito K, Fox N, Kaushansky K · Mol Cell Biol 2004
     used by HOXA9 has its own nuclear bodies, and in monocytic AML they move into the eIF4E body - a subnuclear switch measured in patient marrow and never genotyped
394. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15026366
     Menin inactivation leads to loss of transforming growth factor beta inhibition of parathyroid cell proliferation and parathyroid hormone secretion.

     Sowa H, Kaji H, Kitazawa R, Kitazawa S, Tsukamoto T, Yano S, et al. · Cancer Research 2004
     used by Hypothesis: the PTH rise on menin inhibitors is on-target and exposure-dependent, not renal, Hypothesis: the same drug is protective in the islet and harmful in the parathyroid and the growth plate, Menin is the switch that lets TGF-beta turn parathyroid hormone down - and it works on secretion, not just growth, Nobody needs to enrol anyone: the PTH question is a regression on data that already exists, The cheapest missing experiment in this beat: put revumenib on a parathyroid cell
395. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 14978794
     Protracted postnatal natural histories in childhood leukemia

     Maia AT, Koechling J, Corbett R, Metzler M, Wiemels JL, Greaves M · Genes, Chromosomes & Cancer 2004
     used by In-utero origin, proven: clonotypic KMT2A::AFF1 junctions found in the patient's own newborn blood spot, Latency: months from the fusion forming in a fetus to leukaemia in an infant, against years or a decade for every other backtracked fusion
396. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15302918
     TIP27: a novel repressor of the nuclear orphan receptor TAK1/TR4

     Nakajima T, Fujino S, Nakanishi G, Kim YS, Jetten AM · Nucleic Acids Res 2004
     used by 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
397. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 14992727
     Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus.

     Hughes CM, Rozenblatt-Rosen O, Milne TA, et al. · Mol Cell 2004
     used by KMT2B (MLL2/MLL4) - the other protein menin binds, and the one this graph never wrote
398. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 14671638
     Malignant hematopoietic cell lines: in vitro models for the study of MLL gene alterations.

     Drexler HG, Quentmeier H, MacLeod RA · Leukemia 2004
     used by 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
399. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 14713950
     Hematopoietic, angiogenic and eye defects in Meis1 mutant animals.

     Hisa T, Spence SE, Rachel RA, Fujita M, Nakamura T, Ward JM, Devor-Henneman DE, Saiki Y, Kutsuna H, Tessarollo L, Jenkins NA, Copeland NG · EMBO Journal 2004
     used by MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed
400. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15105502
     MicroRNA-directed cleavage of HOXB8 mRNA

     Yekta S, Shih IH, Bartel DP · Science 304(5670):594-6 2004
     used by miR-196b — the HOXA-cluster microRNA that is a direct KMT2A-fusion target and a genuine double agent
401. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15217837
     Elevated expression of the AF1q gene, an MLL fusion partner, is an independent adverse prognostic factor in pediatric acute myeloid leukemia.

     Tse W, Meshinchi S, Alonzo TA, Stirewalt DL, Gerbing RB, Woods WG, et al. · Blood 2004
     used by MLLT11 / AF1q — a 90-residue protein with no chromatin domain and no oligomerisation module, KMT2A partner in t(1;11)(q21;q23)
402. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 14656882
     Vdelta2-Jalpha rearrangements are frequent in precursor-B-acute lymphoblastic leukemia but rare in normal lymphoid cells.

     Szczepanski T, van der Velden VH, Hoogeveen PG, et al. · Blood 2004
     used by MRD by Ig/TCR rearrangement: the standard in ALL, and the assay infant KMT2A-rearranged disease strains hardest
403. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 14988005
     Neurofibromin is actively transported to the nucleus.

     Vandenbroucke I, Van Oostveldt P, Coene E, De Paepe A, Messiaen L · FEBS Lett 2004
     used by NF1 - the only tumour-suppressor loss in this disease, and it is a deletion, so a mutation panel cannot see it
404. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 15036893
     A t(11;20)(p15;q11) may identify a subset of nontherapy-related acute myelocytic leukemia

     Potenza L, et al. · Cancer Genetics and Cytogenetics 2004
     used by NUP98::TOP1, t(11;20)(p15;q11~q12) — the most precisely mapped NUP98 breakpoint, and the reciprocal that was wrong twice
405. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15169904
     Role of pescadillo and upstream binding factor in the proliferation and differentiation of murine myeloid cells.

     Prisco M, et al. · Mol Cell Biol 2004
     used by PES1 / pescadillo (O00541) - the missing PeBoW subunit of this graph's nucleolar block, pan-essential in 96.9% of DepMap lines, and the one myeloid experiment on it shows proliferation WITHOUT a differentiation block
406. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15105503
     Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD.

     Budanov AV, Sablina AA, Feinstein E, et al. · Science 2004
     used by SESN2 / sestrin-2 (P58004) - the ISR's exit into mTORC1: a leucine sensor that falls 1.4 log2 under either inhibitor, and the one panel member with a real structural record
407. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15239126
     Aberrant intracellular localization of SET-CAN fusion protein, associated with a leukemia, disorganizes nuclear export.

     Saito S; Miyaji-Yamaguchi M; Nagata K · Int J Cancer 2004
     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
408. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 15235609
     SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells.

     Hamamoto R, Furukawa Y, et al. · Nat Cell Biol 2004
     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
409. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15146183
     Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1.

     Rosenbauer F, Wagner K, Kutok JL, Iwasaki H et al. · Nat Genet 2004
     used by SPI1 / PU.1 — a myeloid dependency that a KMT2A panel mistakes for its own
410. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 14990976
     Modulation of cell cycle by graded expression of MLL-AF4 fusion oncoprotein.

     Caslini C, Serna A, Rossi V, Introna M, Biondi A · Leukemia 2004
     used by The non-synchronisable state: five KMT2A-rearranged lines refuse mimosine, double thymidine and nocodazole, and the fusion protein does not fluctuate through the cycle
411. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 15361872
     Active genes dynamically colocalize to shared sites of ongoing transcription

     Osborne CS, Chakalova L, Brown KE, Carter D, Horton A, Debrand E, Goyenechea B, Mitchell JA, Lopes S, Reik W, Fraser P · Nature Genetics 2004
     used by 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)
412. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 15130940
     Dimerization: a versatile switch for oncogenesis.

     So CW, Cleary ML · Blood 2004
     used by What is actually conserved across KMT2A partner classes — forced self-association, with two documented exceptions that break the rule
413. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15297313
     Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation.

     Kosaka Y, Koh K, Kinukawa N, Wakazono Y, Isoyama K, Oda T, Hayashi Y, Ohta S, et al. · Blood 2004
     used by Who gets transplanted in infant KMT2A-rearranged ALL, and whether it helps - four criteria, and a literature that points both ways
414. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12957285
     Dimerization contributes to oncogenic activation of MLL chimeras in acute leukemias.

     So CW, Lin M, Ayton PM, et al. · Cancer Cell 2003
     used by ABI1 (Abl interactor 1 / e3B1) — WAVE-complex cytoskeletal adaptor, KMT2A partner, and an ENL-binding protein, EPS15 (AF1p): the EH domains may or may not be discarded, and either way nobody has shown it matters, EPS15 / AF1p — domain architecture, and the one coordinate nobody has published, Experiment: does AF1q self-associate, and does KMT2A::MLLT11 transform? The two measurements nobody has made on the 10th most common KMT2A fusion, GAS7 — growth-arrest-specific F-BAR protein, the second pillar of the forced-oligomerisation model, Hypothesis — the elongation hijack is how one partner class satisfies a more general requirement, and the general requirement is what should be drugged, Hypothesis: tubulin/microtubule association is a recurrent, unnamed property of the KMT2A partners whose transforming module has no other assignment, KMT2A::AFDN (MLL-AF6), t(6;11)(q27;q23), KMT2A::AFF1 oligomerises through the retained AFF1 CHD, putting the commonest fusion in the oligomerisation class, KMT2A::EPS15 (MLL-AF1p), t(1;11)(p32;q23) — the infant-ALL cytoplasmic partner, KMT2A::GAS7 (MLL-GAS7), t(11;17)(q23;p13) — three patients, and the best mouse model in the partner class, KMT2A::SEPTIN6 (MLL-SEPT6), t(X;11)(q24;q23) and its cryptic insertion variants, Separation-of-function test: does KMT2A::AFF1 need its C-terminal homology domain to dimerise?, What is actually conserved across KMT2A partner classes — forced self-association, with two documented exceptions that break the rule
415. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12654251
     Structural basis for the autoinhibition of c-Abl tyrosine kinase

     Nagar B, Hantschel O, Young MA, et al. · Cell 2003
     used by ABL1 — domain architecture and residue coordinates (with the 1a/1b numbering trap)
416. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12665594
     ASAP, a novel protein complex involved in RNA processing and apoptosis

     Schwerk C, Prasad J, Degenhardt K, et al. · Molecular and Cellular Biology 2003
     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
417. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12665971
     Polymorphisms in the MLL breakpoint cluster region (BCR)

     Echlin-Bell DR, Smith LL, Li L, Strissel PL, Strick R, Gupta V, Banerjee J, Larson R, Relling MV, Raimondi SC, Hayashi Y, Taki T, Zeleznik-Le N, Rowley JD · Human Genetics 2003
     used by Alu repeats and nuclear-matrix anchors in the KMT2A breakpoint region — the genome-feature side of the break, Analysis (runnable): is anything actually enriched at KMT2A breakpoints? The test has never been run against a background that could say no, Analysis (runnable): mine the KMT2A junction sequences for repair-pathway signature, and count the one junction class with a genetic control behind it
418. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12800152
     Prenatal chromosomal diversification of leukemia in monozygotic twins

     Kempski H, Mensa-Bonsu KA, Kearney L, Jalali GR, Hann I, Khurshid M, Greaves M · Genes, Chromosomes & Cancer 2003
     used by Are the fusions temporary? No: the KMT2A fusion is the one thing that does not change between diagnosis and relapse, The prevention window: the break happens in a fetus, and we know when it CLOSES but not when it opens, Twin concordance: near-total for infant KMT2A-rearranged leukaemia, about 5% for childhood ALL overall
419. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12814551
     ATR kinase activity regulates the intranuclear translocation of ATR and RPA following ionizing radiation.

     Barr SM, Leung CG, Chang EE, Cimprich KA · Curr Biol 2003
     used by ATR - the replication-stress kinase with the best preclinical case in this disease and the best published reason not to inhibit it, Where RPA actually is: nucleoplasmic and diffuse until there is single-stranded DNA, then punctate prereplication foci at the G1/S border, damage-induced foci with RAD51, and a PML-body pool - and the subunits differ in how well any of this is measured
420. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12714970
     Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells

     Lessard J, Sauvageau G · Nature 423:255-260 2003
     used by BMI1 - the self-renewal gene that KMT2A fusions can do without, because HOXA9 covers for it at the same locus, BMI1, CDKN2A and CDK6 are one circuit, not three genes - and in KMT2A-rearranged disease it has a loop nobody has measured
421. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12941803
     Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice

     Bertolino P, Tong WM, Herrera PL, Casse H, Zhang CX, Wang ZQ · Cancer Res 63:4836-41 2003
     used by Both approved menin inhibitors cause multi-organ hyperplasia in animals, and one of them in the pancreas irreversibly, How long does menin have to be gone? Two months in a mouse islet, a decade or more in a human carrier, Pancreatic neuroendocrine tumours in MEN1: the manifestation that kills, and the one the animal data points at, Turn menin off for a defined window, then back on: the missing experiment that would bound reversibility
422. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12810254
     Cytogenetics, fluorescence in situ hybridization, and reverse transcriptase polymerase chain reaction are necessary to clarify the various mechanisms leading to an MLL-AF10 fusion in acute myelocytic leukemia with 10;11 rearrangement

     Klaus M, Schnittger S, Haferlach T, et al. · Cancer Genetics and Cytogenetics 2003
     used by Breakpoint anatomy, and an audit of the prognosis claim
423. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12807883
     Mutagenesis of the Runt domain defines two energetic hot spots for heterodimerization with the core binding factor beta subunit

     Zhang L, Li Z, Yan J, et al. · Journal of Biological Chemistry 2003
     used by CBFB — domain architecture and residue coordinates, RUNX1 — domain architecture and residue coordinates (with the RUNX1b/RUNX1c +27 offset)
424. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 14706337
     Requirement for cyclin D3 in lymphocyte development and T cell leukemias.

     Sicinska E, Aifantis I, Le Cam L, Swat W, Borowski C, Yu Q, Ferrando AA, Levin SD, Geng Y, von Boehmer H, Sicinski P · Cancer Cell 2003
     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
425. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12886247
     Expression of the human homologue of rat NG2 in adult acute lymphoblastic leukemia: close association with MLL rearrangement and a CD10(-)/CD24(-)/CD65s(+)/CD15(+) B-cell phenotype.

     Schwartz S, Rieder H, Schlager B, Burmeister T, Fischer L, Thiel E · Leukemia 2003
     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, 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, 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, CD65s (VIM-2, sialylated ceramide dodecasaccharide) - the myeloid antigen that, with CD15, makes NG2 a perfect predictor of KMT2A rearrangement, CSPG4 / NG2 - the flow-cytometry surrogate for a broken KMT2A, and a direct target gene of the fusion that makes it, DNTT (TdT) - a real gene the graph calls by its enzyme nickname, and TdT-negativity is 100% KMT2A-rearranged in the largest paediatric series, 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, Step 2: flow cytometry and the CD10-negative pro-B fingerprint, The immunophenotype beat's own ledger: what was enumerated, what was written, what was dropped and why, and what could not be read, The named-but-unwritten queue is keyed on gene symbols, so CD15 is invisible to it at 23 entries, What an immunophenotype can and cannot tell you about a genotype - the arithmetic of a surrogate marker, worked on NG2
426. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12886241
     Low expression of the myeloid differentiation antigen CD65s, a feature of poorly differentiated AML in older adults: study of 711 patients enrolled in ECOG trials.

     Paietta E, Neuberg D, Bennett JM, Dewald G, Rowe JM, Cassileth PA, et al. · Leukemia 2003
     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, CD65s (VIM-2, sialylated ceramide dodecasaccharide) - the myeloid antigen that, with CD15, makes NG2 a perfect predictor of KMT2A rearrangement, DNTT (TdT) - a real gene the graph calls by its enzyme nickname, and TdT-negativity is 100% KMT2A-rearranged in the largest paediatric series
427. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12676962
     Regulation of Chk1 includes chromatin association and 14-3-3 binding following phosphorylation on Ser-345.

     Jiang K, Pereira E, Maxfield M, Russell B, Goudelock DM, Sanchez Y · J Biol Chem 2003
     used by CHEK1 (CHK1) - the node where this graph's chidamide synergy actually lands, and the reason that synergy is an HR-impairment argument
428. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12789342
     Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression.

     Yamamoto Y, Verma UN, Prajapati S, Kwak YT, Gaynor RB · Nature 2003
     used by CHUK (IKK-alpha) — the only kinase that sits in BOTH NF-kB arms, which makes it the one subunit whose inhibition has an ambiguous sign in this disease
429. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 14517221
     Functional and structural basis of carnitine palmitoyltransferase 1A deficiency.

     Gobin S, Thuillier L, Jogl G et al · Journal of Biological Chemistry 2003
     used by 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
430. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12950107
     Spermatogenesis of mice lacking CK2alpha': failure of germ cell survival and characteristic modifications of the spermatid nucleus.

     Escalier D, Silvius D, Xu X · Mol Reprod Dev 2003
     used by CSNK2A2 - CK2's other catalytic subunit, expressed in every KMT2A-rearranged line and, if anything, slightly favourable to lose
431. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12406912
     Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia.

     Stam RW, den Boer ML, Meijerink JP, Ebus ME, Peters GJ, Noordhuis P, et al. · Blood 2003
     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
432. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12637473
     Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Société Française d'Oncologie Pédiatrique.

     Le Deley MC, Leblanc T, Shamsaldin A, Raquin MA, Lacour B, Sommelet D, et al. · J Clin Oncol 2003
     used by 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, 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
433. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12960363
     Transcription factor JunD, deprived of menin, switches from growth suppressor to growth promoter

     Agarwal SK, Novotny EA, Crabtree JS, Weitzman JB, Yaniv M, Burns AL, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ · Proc Natl Acad Sci U S A 100:10770-5 2003
     used by Does revumenib displace JunD, and at what concentration relative to KMT2A? (The yes/no half is already answered), JUND - the AP-1 subunit menin holds down, and the one a menin inhibitor lets go, JUND liberation — the drug's mechanism of action and one of its mechanisms of resistance are the same event, Releasing JunD does not merely de-repress it: JunD without menin becomes a growth promoter
434. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 14522254
     Dimerization of MLL fusion proteins immortalizes hematopoietic cells

     Martin ME, Milne TA, Bloyer S, Galoian K, Shen W, Gibbs D, Brock HW, Slany R, Hess JL · Cancer Cell 4(3):197-207 2003
     used by Does the fusion 'lose restraint'? The pattern of KMT2A-side loss, and why the tidy reading does not survive contact with the ledger, Experiment: does AF1q self-associate, and does KMT2A::MLLT11 transform? The two measurements nobody has made on the 10th most common KMT2A fusion, Hypothesis: tubulin/microtubule association is a recurrent, unnamed property of the KMT2A partners whose transforming module has no other assignment, KMT2A::GPHN (MLL-gephyrin), t(11;14)(q23;q24) — the 15-residue counterexample
435. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12686606
     ELL and EAF1 are Cajal body components that are disrupted in MLL-ELL leukemia

     Polak PE, Simone F, Kaberlein JJ, Luo RT, Thirman MJ · Molecular Biology of the Cell 14(4):1517-28 2003
     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 is in Cajal bodies - or nuclear speckles, depending which paper you read - and the MLL-ELL fusion empties them
436. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12446457
     ELL-associated factor 2 (EAF2), a functional homolog of EAF1 with alternative ELL binding properties.

     Simone F, Luo RT, Polak PE, Kaberlein JJ, Thirman MJ · Blood 2003
     used by ELL is in Cajal bodies - or nuclear speckles, depending which paper you read - and the MLL-ELL fusion empties them, ELL: the discarded N-terminal EAF-binding site, and a second subtraction the graph had not recorded — the fusion delocalises endogenous EAF1, KMT2A::ELL (MLL-ELL), t(11;19)(q23;p13.1)
437. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12682286
     Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells.

     · Proc Natl Acad Sci U S A 2003
     used by ESR1 / estrogen receptor alpha - menin's best-documented non-leukaemic partner, and the only one a menin inhibitor is being given to patients to disrupt on purpose
438. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 12791663
     Leukemia in twins: lessons in natural history.

     Greaves MF, Maia AT, Wiemels JL, Ford AM · Blood 2003
     used by ETV6::RUNX1 (TEL-AML1), t(12;21)(p13;q22), Hypothesis: the second hit in infant KMT2A-rearranged leukaemia is a fetal developmental window, not a mutation, Twin concordance: near-total for infant KMT2A-rearranged leukaemia, about 5% for childhood ALL overall, When one thing goes wrong, do several? In infant KMT2A-rearranged leukaemia the answer is no, and that cuts against the intuition
439. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12594313
     Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone

     Grier HE, Krailo MD, Tarbell NJ, et al. · New England Journal of Medicine 2003
     used by EWSR1::FLI1 (EWS-FLI1), t(11;22)(q24;q12)
440. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 14615372
     Hoxa9 influences the phenotype but not the incidence of Mll-AF9 fusion gene leukemia

     Kumar AR, Hudson WA, Chen W, Nishiuchi R, Yao Q, Kersey JH · Blood 2003
     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, How much HOXA9 and MEIS1 is actually required? Partial dependence, a Hox code, and why this caps what any single target can do, HOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it, Hypothesis: the fusion output program fails at a threshold on total cut-set suppression, so three nodes at 40% beat one node at 90%, Necessary is not explanatory: four different questions that a knockout answers as if they were one, The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential
441. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 14636557
     Taspase1: a threonine aspartase required for cleavage of MLL and proper HOX gene expression

     Hsieh JJ, et al. · Cell 2003
     used by 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, Lost from the KMT2A half: both taspase1 cleavage sites (D2666 and D2718) - the fusion is never processed, TASP1 (taspase1) - the protease that cuts KMT2A, and the timer the fusion escapes, 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, 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
442. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12482972
     Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments that confers protein stability and subnuclear localization

     Hsieh JJ, et al. · Molecular and cellular biology 2003
     used by 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, KMT2A / MLL1 — the gene that breaks, 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, 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, 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
443. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12874027
     Menin associates with FANCD2, a protein involved in repair of DNA damage.

     Jin S, Mao H, Schnepp RW, Sykes SM, Silva AC, D'Andrea AD, Hua X · Cancer Res 2003
     used by FANCD2 — the FA effector menin binds, and the weakest FA gene in this graph's own selectivity scan, Fifth explanation for the Fanconi signal: it runs through menin binding FANCD2, not crosslink repair — tested, refuted, prior 0.07, MEN1 / menin — the adaptor the fusion cannot work without, Menin has no subnuclear compartment, and nobody has looked - the whole published record is two biochemical fractionations, both DNA-damage papers, and no microscopy at all, Menin-FANCD2: one 2003 co-immunoprecipitation, a curated sufficient region of menin 214-390, and nothing since, Of 262 curated interactors this graph never wrote down, five are selectively required in KMT2A-rearranged lines - and one of them is FANCD2, which binds menin and sits inside a selectivity signal this project has failed four times to explain, UniProt's menin 214-390 FANCD2 region is not a surface: it spans three spatial lobes and 29.9% of menin's solvent-accessible area, so its twenty-residue overlap with the gamma-H2A.X motif is what chance gives you
444. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 14617007
     Bi-allelic silencing of the Fanconi anaemia gene FANCF in acute myeloid leukaemia.

     Tischkowitz M, Ameziane N, et al. · Br J Haematol 2003
     used by FANCF — FA core complex; rank 11 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
445. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12620411
     Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification.

     Armstrong SA, Kung AL, Mabon ME, Silverman LB, Stam RW, Den Boer ML, Pieters R, Kersey JH, Sallan SE, Fletcher JA, Golub TR, Griffin JD, Korsmeyer SJ · Cancer Cell 2003
     used by FLT3 / CD135 — the strongest non-tether co-dependency, and a target the field may have written off on a badly executed trial, FLT3 in KMT2A-r leukemia — near-universal overexpression, but activating mutation in only ~3% of infants, FLT3 is the second largest KMT2A-selective dependency and it is HEAVIER in B-lineage than in myeloid cells
446. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12620410
     MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice.

     So CW, Karsunky H, Passegué E, Cozzio A, Weissman IL, Cleary ML · Cancer Cell 2003
     used by GAS7 — growth-arrest-specific F-BAR protein, the second pillar of the forced-oligomerisation model, KMT2A::GAS7 (MLL-GAS7), t(11;17)(q23;p13) — three patients, and the best mouse model in the partner class
447. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 12874834
     Gfi-1 attaches to the nuclear matrix, associates with ETO (MTG8) and histone deacetylase proteins, and represses transcription using a TSA-sensitive mechanism.

     McGhee L, Bryan J, Elliott L, Grimes HL, Kazanjian A, Davis JN, Meyers S · J Cell Biochem 2003
     used by GFI1 — the repressor that LSD1 inhibitors actually work through, and the scan hit whose literature points the opposite way
448. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12496962
     Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement.

     Su IH, Basavaraj A, Krutchinsky AN, Hobert O, Ullrich A, Chait BT, et al. · Nat Immunol 2003
     used by Giving a translocation-promoting epigenetic drug in a translocation-defined B-lineage leukaemia, to infants
449. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12663727
     Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study

     Oeffinger KC, Mertens AC, Sklar CA, Yasui Y, Fears T, Stovall M, Vik TA, Inskip PD, Robison LL · Journal of Clinical Oncology 2003
     used by Growth and endocrine consequences of being treated for leukemia as a baby
450. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12670868
     Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1.

     · Genes Dev 2003
     used by HCFC1 (HCF-1) — a founding member of the wild-type KMT2A complex that the fusion cannot bind
451. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 14580347
     Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA.

     Yik JH, Chen R, Nishimura R, Jennings JL, Link AJ, Zhou Q · Mol Cell 2003
     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, 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, The 7SK snRNP - a stable RNA core with a reversibly docked kinase, which is why the reservoir is a switch and not a sink
452. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12676784
     CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCRgammadelta lineage.

     Asnafi V, et al. · Blood 2003
     used by How common PICALM::MLLT10 is, and in which disease - 65% T-ALL, 27% AML, and invisible to karyotype half the time, PICALM::MLLT10 (CALM-AF10), t(10;11)(p13;q14) - the DOT1L-dependent HOXA fusion that contains no KMT2A, The cell CALM-AF10 arrests: an early T-precursor in adults and a TCR-positive thymocyte in children - two states, split by age (corrected 2026-09-21), Where the break falls, and the three incompatible numbering frames that make it easy to get wrong
453. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12923056
     Structure of HoxA9 and Pbx1 bound to DNA: Hox hexapeptide and DNA recognition anterior to posterior

     LaRonde-LeBlanc NA, Wolberger C · Genes & Development 17:2060-2072 2003
     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
454. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12952893
     Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9

     Ayton PM, Cleary ML · Genes & Development 17:2298-2307 2003
     used by HOXA7 - the one HOXA paralogue besides HOXA9 with a published loss-of-function requirement for MLL-fusion transformation, and the requirement was shown in vitro only
455. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12660384
     A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome

     Cools J, DeAngelo DJ, Gotlib J, et al. · New England Journal of Medicine 2003
     used by Imatinib: one molecule, three unrelated rare diseases, twenty years of cross-subsidy
456. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 13679531
     Developmental pharmacology--drug disposition, action, and therapy in infants and children.

     Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE · The New England Journal of Medicine 2003
     used by Infants are not small children - four maturing organ systems, three conditioning drugs, and a protocol that treats the first year of life as one category
457. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12859901
     The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor.

     Gozani O, Karuman P, Jones DR, Ivanov D, Cha J, Lugovskoy AA, Baird CL, Zhu H, Field SJ, Lessnick SL, Villasenor J, Mehrotra B, Chen J, Rao VR, Brugge JS, Ferguson CG, Payrastre B, Myszka DG, Cantley LC, Wagner G, Divecha N, Prestwich GD, Yuan J · Cell 2003
     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, PIP4K2A - the lipid kinase at a genome-wide childhood-ALL susceptibility locus, whose product is the ligand a PHD finger reads
458. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 12527918
     The human LASP1 gene is fused to MLL in an acute myeloid leukemia with t(11;17)(q23;q21).

     Strehl S, Borkhardt A, Slany R, Fuchs UE, König M, Haas OA · Oncogene 2003
     used by KMT2A::MLLT6 (MLL-AF17), t(11;17)(q23;q12-q21) — the bridge case: a leucine zipper on a DOT1L-complex subunit
459. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12874781
     MLL/SEPTIN6 chimeric transcript from inv ins(X;11)(q24;q23q13) in acute monocytic leukemia: report of a case and review of the literature.

     Kim HJ, Ki CS, Park Q, et al. · Genes Chromosomes Cancer 2003
     used by KMT2A::SEPTIN6 (MLL-SEPT6), t(X;11)(q24;q23) and its cryptic insertion variants
460. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12646957
     TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23).

     Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR · Leukemia 2003
     used by KMT2A::TET1 (MLL-LCX), t(10;11)(q22;q23) — the fusion that throws away a second CXXC domain, TET1 (LCX / CXXC6) - a CXXC reader that is also a KMT2A fusion partner, and whose leukaemic fusion throws its own CXXC domain away
461. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 14564000
     LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1

     Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, et al. · Science 302:415-419 2003
     used by LMO2 (rhombotin-2) - a bridging LIM-only protein, higher in pro-B and MLL-rearranged B-ALL, anti-selective in KMT2A-rearranged lines, and a physical partner of the KDM5A module that NUP98::KDM5A retains
462. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12509449
     The 32-kilodalton subunit of replication protein A interacts with menin, the product of the MEN1 tumor suppressor gene.

     Sukhodolets KE, Hickman AB, Agarwal SK, Sukhodolets MV, Obungu VH, Novotny EA, Crabtree JS, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL, Marx SJ · Molecular and Cellular Biology 23(2):493-509 2003
     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, RPA1 (RPA70) - the large subunit of replication protein A, which carries most of the ssDNA-binding folds and the N-terminal fold that hands the lesion to ATR, RPA2 (RPA32) - the middle subunit of replication protein A, whose disordered N-terminus is the phospho-switch of the replication-stress response and whose 43-171 region binds menin, Where RPA actually is: nucleoplasmic and diffuse until there is single-stranded DNA, then punctate prereplication foci at the G1/S border, damage-induced foci with RAD51, and a PML-body pool - and the subunits differ in how well any of this is measured
463. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 12649288
     Inactivation of menin, the product of the multiple endocrine neoplasia type 1 gene, inhibits the commitment of multipotential mesenchymal stem cells into the osteoblast lineage.

     Sowa H, Kaji H, Canaff L, Hendy GN, Tsukamoto T, Yamaguchi T, et al. · Journal of Biological Chemistry 2003
     used by Menin builds bone early and blocks it late: two opposite jobs in the same lineage, The label says monitor bone growth in children. Not one paper has asked what menin does in a growth plate
464. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 14508515
     Menin, a tumor suppressor, associates with nonmuscle myosin II-A heavy chain.

     Obungu VH, Lee Burns A, Agarwal SK, Chandrasekharapa SC, Adelstein RS, Marx SJ · Oncogene 2003
     used by MYH9 (non-muscle myosin IIA) — the best-validated menin partner nobody in this field talks about, and the only one that maps to menin's N-terminus
465. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12509435
     Overexpression of the Linker histone-binding protein tNASP affects progression through the cell cycle.

     Alekseev OM, Bencic DC, Richardson RT, Widgren EE, O'Rand MG · J Biol Chem 2003
     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
466. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12874791
     Both NUP98/TOP1 and TOP1/NUP98 transcripts are detected in a de novo AML with t(11;20)(p15;q11)

     Iwase S, et al. · Genes, Chromosomes & Cancer 38(1):102-105 2003
     used by NUP98::TOP1, t(11;20)(p15;q11~q12) — the most precisely mapped NUP98 breakpoint, and the reciprocal that was wrong twice
467. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 14574413
     Osteoblastic cells regulate the haematopoietic stem cell niche

     Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, et al. · Nature 2003
     used by Osteoblast — the bone-building niche cell whose expansion suppresses CML and makes MLL-AF9 AML worse, The bone-marrow niche — the address a blood stem cell lives at, which 26 entries in this graph invoke and none had defined, The endosteal niche — the bone surface, where leukaemia-initiating cells were imaged homing and dividing symmetrically
468. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 14574412
     Identification of the haematopoietic stem cell niche and control of the niche size

     Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, et al. · Nature 2003
     used by Osteoblast — the bone-building niche cell whose expansion suppresses CML and makes MLL-AF9 AML worse, The endosteal niche — the bone surface, where leukaemia-initiating cells were imaged homing and dividing symmetrically
469. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12876293
     The Rtf1 component of the Paf1 transcriptional elongation complex is required for ubiquitination of histone H2B.

     Ng HH, Dole S, Struhl K · J Biol Chem 2003
     used by PAF1C couples transcription to H2B ubiquitination - but the RTF1 half of that coupling is yeast-specific and contested in human cells, and PAF1C is one of the few complexes that genuinely binds the retained KMT2A fragment, Separation-of-function RTF1 rescue in a KMT2A-fusion line: does the fusion need PAF1C for elongation, or for H2B ubiquitination?
470. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 12724421
     Nonmuscle myosin promotes cytoplasmic localization of PBX

     Huang H, Paliouras M, Rambaldi I, Lasko P, Featherstone M · Molecular and Cellular Biology 23:3636-3645 2003
     used by PBX proteins are not constitutively nuclear: a MEINOX partner keeps them there by blocking export - and nobody has ever looked at PBX3 in a KMT2A-rearranged cell
471. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12808040
     RNA polymerase III transcripts and the PTB protein are essential for the integrity of the perinucleolar compartment.

     · Mol Biol Cell 2003
     used by 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
472. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12791985
     Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.

     Zou L, Elledge SJ · Science 300(5625):1542-8 2003
     used by RPA-coated single-stranded DNA is the structure that licenses ATR: ATRIP reads it, ATR is brought to the lesion, and CHK1 is activated - which is how this corpus's ATR and CHEK1 entries connect to the clamp that had no entry until now, RPA1 (RPA70) - the large subunit of replication protein A, which carries most of the ssDNA-binding folds and the N-terminal fold that hands the lesion to ATR, The replication protein A heterotrimer (RPA1/RPA2/RPA3) - the ssDNA clamp that every resection and replication-stress claim in this corpus silently depends on, and which had no entry until cycle 160
473. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12807882
     Energetic contribution of residues in the Runx1 Runt domain to DNA binding

     Li Z, Yan J, Matheny CJ, et al. · Journal of Biological Chemistry 2003
     used by RUNX1 — domain architecture and residue coordinates (with the RUNX1b/RUNX1c +27 offset)
474. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12692553
     Tissue-specific nuclear architecture and gene expression regulated by SATB1

     Cai S, Han HJ, Kohwi-Shigematsu T · Nat Genet 2003
     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
475. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12496757
     Mutations in SBDS are associated with Shwachman-Diamond syndrome.

     Boocock GR, et al. · Nat Genet 2003
     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
476. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 14648661
     Altered expression of the septin gene, SEPT9, in ovarian neoplasia.

     Burrows JF, Chanduloy S, McIlhatton MA, et al. · J Pathol 2003
     used by SEPTIN9 (septin-9 / MSF) — cytoskeletal GTPase, KMT2A fusion partner in t(11;17)(q23;q25)
477. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12750700
     Cryptic insertion and translocation or nondividing leukemic cells disclosed by FISH analysis in infant acute leukemia with discrepant molecular and cytogenetic findings

     Watanabe N, Kobayashi H, Ichiji O, Yoshida MA, Kikuta A, Komada Y, Sekine I, Ishida Y, Horiukoshi Y, Tsunematsu Y, Yano M, Nakadate H, Kaneko Y · Leukemia 2003
     used by Step 3: the G-banded karyotype and t(4;11)(q21;q23), Step 4: the split-signal FISH nucleus - one fusion, one green, one red
478. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 15070701
     Regulation of annexin II by cytokine-initiated signaling pathways and E2A-HLF oncoprotein

     Matsunaga T, Inaba T, Matsui H, Okuya M, Miyajima A, Inukai T, Funabiki T, Endo M, Look AT, Kurosawa H · Blood 2003
     used by TCF3::HLF (E2A-HLF), t(17;19)(q22;p13)
479. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12781363
     Engineering de novo reciprocal chromosomal translocations associated with Mll to replicate primary events of human cancer.

     Forster A, Pannell R, Drynan LF, et al. · Cancer Cell 2003
     used by The most faithful mouse models of t(11;19) are reciprocal-positive by design, and the commonest ones carry no reciprocal allele at all - and nobody has compared them
480. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 14633735
     Parathyroid gland-specific deletion of the mouse Men1 gene results in parathyroid neoplasia and hypercalcemic hyperparathyroidism.

     Libutti SK, Crabtree JS, Lorang D, Burns AL, Mazzanti C, Hewitt SM, et al. · Cancer Research 2003
     used by The parathyroid does not need the rest of the body: deleting menin only there causes neoplasia and hypercalcaemia
481. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12629167
     A mutation in Af4 is predicted to cause cerebellar ataxia and cataracts in the robotic mouse.

     Isaacs AM, Oliver PL, Jones EL, Jeans A, Potter A, Hovik BH, Nolan PM, Vizor L, Glenister P, Simon AK, Gray IC, Spurr NK, Brown SD, Hunter AJ, Davies KE · The Journal of Neuroscience 2003
     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
482. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12810724
     The promyelocytic leukemia protein protects p53 from Mdm2-mediated inhibition and degradation.

     Louria-Hayon I, Grossman T, Sionov RV, Alsheich O, Pandolfi PP, Haupt Y · J Biol Chem 2003
     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
483. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 12393420
     Temporal gene expression profile of human precursor B leukemia cells induced by adhesion receptor: identification of pathways regulating B-cell survival.

     Astier AL, Xu R, Svoboda M, et al. (9 authors; senior author Freedman AS) · Blood 2003
     used by Two of seven interactome read-queue partners should not get a gene entry, and the reasons are a pseudokinase with no nuclear pool and a membrane-skeleton protein whose two leukaemia hits are a gene-name artefact
484. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12829790
     MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein

     Xia ZB, Anderson M, Diaz MO, Zeleznik-Le NJ · Proceedings of the National Academy of Sciences USA 100(14):8342-8347 2003
     used by What is lost: the PHD3/CYP33 switch that lets wild-type KMT2A turn itself off
485. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12796494
     LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells.

     Maertens G, Cherepanov P, Pluymers W, Busschots K, De Clercq E, Debyser Z, Engelborghs Y · J Biol Chem 2003
     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
486. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11981001
     Favorable impact of the t(9;11) in childhood acute myeloid leukemia.

     Rubnitz JE, Raimondi SC, et al. · J Clin Oncol 2002
     used by 756 children with 11q23/MLL-rearranged AML: 5-year EFS runs from 11% to 92% depending on the partner, KMT2A::MLLT3 / t(9;11): the best-known partner prognosis claim, and the three cohorts that did not reproduce it, KMT2A::MLLT3 across 612 genotyped patients: myeloid at every age, but 248 of them have ALL, and 157 of those are infants
487. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11842107
     The MT domain of the proto-oncoprotein MLL binds to CpG-containing DNA and discriminates against methylation

     Birke M, Schreiner S, Garcia-Cuellar MP, Mahr K, Titgemeyer F, Slany RK · Nucleic Acids Research 2002
     used by Analysis: test whether published KMT2A::AFF1 occupancy is enriched at scaffold-attachment and cruciform-prone DNA beyond what CpG islands explain, IDH2 - the hypermethylating co-mutation that IS enriched in KMT2A-rearranged AML (16.0% vs 10.4%), at p = 0.0004 and not the p < 0.0001 the abstract claims, If the fusion's address requires unmethylated CpG, a hypermethylating co-mutation should be selected AGAINST - and IDH2 is selected FOR, which means the address is not the limiting resource, LPP (lipoma-preferred partner) - a KMT2A fusion partner in acute monoblastic leukaemia whose day job is adhesion mechanotransduction, and which is barely expressed in leukocytes, One afternoon of titrations that closes a 1,300-fold question: tagless 1147-1203 against tagless 1147-1244, matched in every other respect, One domain, two names - and `MLL[tiab]` does not match `MLL1`. Two token traps, two missing affinity papers each, Rerun the 2002 SPR with the two controls it did not have: cleave the GST, and put the protein on the chip instead of the DNA, Ten affinity measurements for this contact and not one uses a fusion protein, full-length KMT2A or a nucleosome, The 41 residues after the CXXC fold (1204-1244) carry a substantial part of the fusion's DNA grip, and removing them is why the structural literature's affinity is so low, The CXXC domain (aa 1147-1195, PDB 2KKF) is a chromatin address, not a compartment address — CpG mutants lose transformation but keep their subnuclear position, 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, The measurement everybody said was missing exists: in SEM cells KMT2A::AFF1 occupies 20% of unmethylated CpG sites, CXXC1 50% and KDM2B 89%, and only the fusion tracks menin (r2 = 0.96), The MT/BCB domain, Q03164 1147-1244: the CXXC fold plus a 41-residue basic tail nobody has measured on its own
488. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12434154
     HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome

     Carpten JD, Robbins CM, Villablanca A, et al. · Nature Genetics 2002
     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
489. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11780146
     Structure of the Bcr-Abl oncoprotein oligomerization domain

     Zhao X, Ghaffari S, Lodish H, Malashkevich VN, Kim PS · Nature Structural Biology 2002
     used by BCR — domain architecture and residue coordinates
490. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
     PDB entry 1K1F: Structure of the Bcr-Abl Oncoprotein Oligomerization Domain

     RCSB Protein Data Bank · RCSB PDB 2002
     used by BCR::ABL1 (Philadelphia chromosome), t(9;22)(q34;q11)
491. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12172539
     Altered affinity of CBF beta-SMMHC for Runx1 explains its role in leukemogenesis

     Lukasik SM, Zhang L, Corpora T, Tomanicek S, Li Y, Kundu M, Hartman K, Liu PP, Laue TM, Biltonen RL, Speck NA, Bushweller JH · Nat Struct Biol 2002
     used by CBFB::MYH11 (CBFbeta-SMMHC), inv(16)(p13;q22)
492. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12239155
     Role of Cbfb in hematopoiesis and perturbations resulting from expression of the leukemogenic fusion gene Cbfb-MYH11

     Kundu M, Chen A, Anderson S, Kirby M, Xu L, Castilla LH, Bodine D, Liu PP · Blood 2002
     used by CBFB::MYH11 (CBFbeta-SMMHC), inv(16)(p13;q22)
493. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12057554
     Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region.

     Pui CH, Gaynon PS, et al. · Lancet 2002
     used by CCG 1953 (n=115 infants): the first trial to genotype every infant found the partner does not predict outcome, The age confound: a partner arm and an age arm are nearly the same arm, Who gets transplanted in infant KMT2A-rearranged ALL, and whether it helps - four criteria, and a literature that points both ways
494. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12097915
     AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification

     Petersen-Mahrt SK, Harris RS, Neuberger MS · Nature 2002
     used by Class switch recombination: a B cell deliberately mutates and cuts its own antibody locus, and the same enzyme causes MYC-IgH translocations
495. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12193648
     Prospective isolation of human clonogenic common myeloid progenitors

     Manz MG, Miyamoto T, Akashi K, Weissman IL · Proceedings of the National Academy of Sciences USA 2002
     used by Common myeloid progenitor (CMP) — the fork at which KMT2A leukaemia almost always turns one way, Granulocyte-monocyte progenitor (GMP) — the committed cell an MLL fusion can turn back into a stem cell, Megakaryocyte-erythroid progenitor (MEP) — the branch KMT2A fusions almost never take, which is why it was a usable control
496. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12138111
     A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with active de novo methylation.

     Chen T, Ueda Y, Xie S, Li E · J Biol Chem 2002
     used by DNMT3A - an independent adverse factor in adult KMT2A-rearranged AML and conspicuously absent from paediatric disease, which is the whole finding
497. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 12145218
     Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases.

     Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S · EMBO J 2002
     used by DNMT3A - an independent adverse factor in adult KMT2A-rearranged AML and conspicuously absent from paediatric disease, which is the whole finding
498. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11818576
     Human Elongator facilitates RNA polymerase II transcription through chromatin.

     Kim JH, Lane WS, et al. · Proc Natl Acad Sci U S A 2002
     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, 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, 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
499. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11904415
     Elongator is a histone H3 and H4 acetyltransferase important for normal histone acetylation levels in vivo.

     Winkler GS, Kristjuhan A, et al. · Proc Natl Acad Sci U S A 2002
     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, 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, 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, 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
500. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11714725
     Purification and characterization of the human elongator complex.

     Hawkes NA, Otero G, et al. · J Biol Chem 2002
     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, 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, 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, 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
501. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11889558
     Characterization of a novel gene adjacent to PAX6, revealing synteny conservation with functional significance.

     Kleinjan DA, Seawright A, Elgar G et al · Mammalian Genome 2002
     used by 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
502. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12193272
     Native interface of the SAM domain polymer of TEL

     Tran HH, Kim CA, Faham S, Siddall MC, Bowie JU · BMC Structural Biology 2002
     used by ETV6 — domain architecture and residue coordinates
503. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12450792
     Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma

     Tognon C, Knezevich SR, Huntsman D, et al. · Cancer Cell 2002
     used by ETV6::NTRK3 (ETV6-TRKC), t(12;15)(p13;q25), Is KMT2A::AFF1 leukemia epithelial or endothelial? No — it is haematopoietic. But the question is a good one
504. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 12048236
     Chromosome translocations and covert leukemic clones are generated during normal fetal development

     Mori H, Colman SM, Xiao Z, Ford AM, Healy LE, Donaldson C, Hows JM, Navarrete C, Greaves M · Proc Natl Acad Sci U S A 2002
     used by ETV6::RUNX1 (TEL-AML1), t(12;21)(p13;q22), Newborn screening for leukaemia fusions: verdict NOT FEASIBLE TODAY, and the reason is arithmetic plus the absence of anything to offer a positive, Twin concordance: near-total for infant KMT2A-rearranged leukaemia, about 5% for childhood ALL overall, What fraction of fusion-positive newborns ever get leukaemia? For ETV6::RUNX1, very few. For KMT2A, nobody knows, and the biology says the answer may be most of them
505. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12359745
     Recurrent rearrangement of the Ewing's sarcoma gene, EWSR1, or its homologue, TAF15, with the transcription factor CIZ/NMP4 in acute leukemia.

     Martini A, La Starza R, Janssen H, Bilhou-Nabera C, Corveleyn A, Somers R, Aventin A, Foa R, Hagemeijer A, Mecucci C, Marynen P · Cancer Res 2002
     used by 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, 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, TAF15 (RBP56, TAF2N) - the FET-family, prion-like partner that donates a low-complexity N-terminus to ZNF384, 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, 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
506. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12086603
     Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways.

     Taniguchi T, Garcia-Higuera I, Xu B, Andreassen PR, Gregory RC, Kim ST, Lane WS, Kastan MB, D'Andrea AD · Cell 2002
     used by FANCD2 — the FA effector menin binds, and the weakest FA gene in this graph's own selectivity scan
507. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11731795
     MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia

     Armstrong SA, Staunton JE, Silverman LB, Pieters R, den Boer ML, Minden MD, Sallan SE, Lander ES, Golub TR, Korsmeyer SJ · Nature Genetics 30(1):41-7 2002
     used by FLT3 in KMT2A-r leukemia — near-universal overexpression, but activating mutation in only ~3% of infants, Scott Armstrong & Andrei Krivtsov (Dana-Farber / Boston Children's) — the group that turned menin dependency into a drug, Step 5 — The output program: HOXA9/HOXA10/MEIS1/PBX3 plus MEF2C, MYB, BCL2, FLT3 and PROM1/CD133
508. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11986239
     In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia

     Wiemels JL, Xiao Z, Buffler PA, Maia AT, Ma X, Dicks BM, et al. · Blood 2002
     used by Fusion-positive clones that never become leukaemia: persistence in remission, spontaneous clearance, and silent rearrangements in healthy people, In-utero origin, proven: clonotypic KMT2A::AFF1 junctions found in the patient's own newborn blood spot, Latency: months from the fusion forming in a fetus to leukaemia in an infant, against years or a decade for every other backtracked fusion
509. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12183469
     Two highly related p66 proteins comprise a new family of potent transcriptional repressors interacting with MBD2 and MBD3.

     Brackertz M, Boeke J, Zhang R, Renkawitz R · Journal of Biological Chemistry 2002
     used by GATAD2A / p66-alpha (Q86YP4) - the subunit that bridges NuRD's two modules, the best-ranked NuRD gene in this project's KMT2A-selectivity scan, and present in the pan-fusion interactome under MLL-AF9 but NOT the index fusion, GATAD2B / p66-beta (Q8WXI9) - the NuRD scaffold with the broadest presence in the pan-MLL-fusion interactome, five of seven baits and still not the index fusion, and a haploinsufficiency syndrome that caps any therapeutic idea
510. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12086618
     PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin

     Nishioka K, Rice JC, Sarma K, et al. · Molecular Cell 2002
     used by H4K20me1 - the transcription- and replication-linked H4 state, whose gene-body level tracks Pol II; it HAS been profiled genome-wide in human haematopoietic stem cells twice, and a query scoped to 'leukemia' cannot see either dataset
511. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12226747
     Menin uncouples Elk-1, JunD and c-Jun phosphorylation from MAP kinase activation

     Gallo A, Cuozzo C, Esposito I, Maggiolini M, Bonofiglio D, Vivacqua A, Garramone M, Weiss C, Bohmann D, Musti AM · Oncogene 21:6434-45 2002
     used by How menin silences JunD: pocket binding plus uncoupling from MAP kinase signalling, JUND - the AP-1 subunit menin holds down, and the one a menin inhibitor lets go
512. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12181401
     Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors

     Demetri GD, von Mehren M, Blanke CD, et al. · New England Journal of Medicine 2002
     used by Imatinib: one molecule, three unrelated rare diseases, twenty years of cross-subsidy
513. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 12547160
     Is t(10;11)(p11.2;q23) involving MLL and ABI-1 genes associated with congenital acute monocytic leukemia?

     Morerio C, Rosanda C, Rapella A, et al. · Cancer Genet Cytogenet 2002
     used by KMT2A::ABI1 (MLL-ABI1), t(10;11)(p11.2;q23) — the partner that binds an elongation partner
514. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12096348
     MLL-SEPTIN6 fusion recurs in novel translocation of chromosomes 3, X, and 11 in infant acute myelomonocytic leukaemia and in t(X;11) in infant acute myeloid leukaemia, and MLL genomic breakpoint in complex MLL-SEPTIN6 rearrangement is a DNA topoisomerase II cleavage site.

     Slater DJ, Hilgenfeld E, Rappaport EF, et al. · Oncogene 2002
     used by KMT2A::SEPTIN2 (MLL-SEPT2), t(2;11)(q37;q23) — the therapy-related septin, KMT2A::SEPTIN6 (MLL-SEPT6), t(X;11)(q24;q23) and its cryptic insertion variants
515. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11809673
     SEPTIN6, a human homologue to mouse Septin6, is fused to MLL in infant acute myeloid leukemia with complex chromosomal abnormalities involving 11q23 and Xq24.

     Ono R, Taki T, Taketani T, et al. · Cancer Res 2002
     used by KMT2A::SEPTIN6 (MLL-SEPT6), t(X;11)(q24;q23) and its cryptic insertion variants
516. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12124344
     LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23).

     Ono R, Taki T, Taketani T, Taniwaki M, Kobayashi H, Hayashi Y · Cancer Res 2002
     used by KMT2A::TET1 (MLL-LCX), t(10;11)(q22;q23) — the fusion that throws away a second CXXC domain, TET1 (LCX / CXXC6) - a CXXC reader that is also a KMT2A fusion partner, and whose leukaemic fusion throws its own CXXC domain away
517. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12370315
     Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors.

     Wu L, Sun T, Kobayashi K, Gao P, Griffin JD · Mol Cell Biol 2002
     used by MAML2 (mastermind-like 2) - the Notch co-activator that is a KMT2A partner in leukaemia and in thymoma
518. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12154025
     Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571)

     Nagar B, Bornmann WG, Pellicena P, et al. · Cancer Research 2002
     used by Mechanism class 3 — constitutive kinase activation (BCR::ABL1, NPM1::ALK, ETV6::NTRK3), Why BCR::ABL1 became treatable — and what KMT2A::AFF1 does not share with it
519. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12200353
     A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias.

     Ottmann OG, Druker BJ, Sawyers CL, et al. · Blood 2002
     used by Mechanism class 3 — constitutive kinase activation (BCR::ABL1, NPM1::ALK, ETV6::NTRK3), Why BCR::ABL1 became treatable — and what KMT2A::AFF1 does not share with it
520. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11784856
     The neuronal basic helix-loop-helix transcription factor NSCL-1 is dispensable for normal neuronal development.

     Krüger M, Braun T · Mol Cell Biol 2002
     used by 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
521. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11896389
     Haploinsufficiency of NSD1 causes Sotos syndrome

     Kurotaki N, Imaizumi K, Harada N, Masuno M, et al. · Nat Genet 2002
     used by NSD1 - the H3K36 dimethyltransferase whose catalytic activity a NUP98 fusion cannot do without, and which cells can otherwise lose almost for free
522. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11971817
     The Retinoic acid receptor alpha (RARalpha) chimeric proteins PML-, PLZF-, NPM-, and NuMA-RARalpha have distinct intracellular localization patterns.

     Hummel JL, Wells RA, Dubé ID, Licht JD, Kamel-Reid S · Cell Growth & Differentiation 2002
     used by 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
523. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11950939
     Nup98 is a mobile nucleoporin with transcription-dependent dynamics

     Griffis ER, Altan N, Lippincott-Schwartz J, Powers MA · Mol Biol Cell 2002
     used by NUP98 - the mobile nucleoporin that leaves the pore to put H3K4me3 on haematopoietic promoters, and the shared 5' donor of seven fusions in this graph
524. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12191480
     The three-dimensional structure of the autoproteolytic, nuclear pore-targeting domain of the human nucleoporin Nup98

     Hodel AE, Hodel MR, Griffis ER, et al. · Molecular Cell 2002
     used by NUP98 — domain architecture and residue coordinates (with the 1817/920 numbering trap resolved)
525. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
     PDB entries 1KO6 (Crystal Structure of C-terminal Autoproteolytic Domain of Nucleoporin Nup98) and 2Q5X (Crystal Structure of the C-terminal domain of hNup98)

     RCSB Protein Data Bank · RCSB PDB 2002
     used by NUP98::NSD1, t(5;11)(q35;p15.5)
526. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11875078
     Caspase proteolysis of the cohesin component RAD21 promotes apoptosis.

     Chen F, Kamradt M, Mulcahy M, Byun Y, Xu H, McKay MJ, Cryns VL · J Biol Chem 2002
     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
527. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11927569
     Structure of the RPA trimerization core and its role in the multistep DNA-binding mechanism of RPA.

     Bochkareva E, Korolev S, Lees-Miller SP, Bochkarev A · EMBO Journal 21(7):1855-63 2002
     used by RPA1 (RPA70) - the large subunit of replication protein A, which carries most of the ssDNA-binding folds and the N-terminal fold that hands the lesion to ATR, RPA3 (RPA14) - the 121-residue subunit of replication protein A, which has no annotated domain, no HPA localisation call and no connection to this disease at all, The replication protein A heterotrimer (RPA1/RPA2/RPA3) - the ssDNA clamp that every resection and replication-stress claim in this corpus silently depends on, and which had no entry until cycle 160
528. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12130538
     G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis

     Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H, Shinkai Y · Genes Dev 2002
     used by 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
529. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12006491
     Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence.

     Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, Pelicci PG, Kouzarides T · EMBO J 2002
     used by SIRT1 - not a fusion partner, the least required gene in KMT2A-rearranged lines, and the one target here where the direction of the drug is genuinely disputed
530. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 12398892
     Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo

     Inoue A, Seidel MG, Wu W, Kamizono S, Ferrando AA, Bronson RT, Iwasaki H, Akashi K, Morimoto A, Hitzler JK, Pestina TI, Jackson CW, Tanaka R, Chong MJ, McKinnon PJ, Inukai T, Grosveld GC, Look AT · Cancer Cell 2002
     used by TCF3::HLF (E2A-HLF), t(17;19)(q22;p13)
531. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12167634
     Ubiquitination of histone H2B by Rad6 is required for efficient Dot1-mediated methylation of histone H3 lysine 79.

     Ng HH, Xu RM, Zhang Y, Struhl K · J Biol Chem 2002
     used by The trans-histone crosstalk H2Bub → DOT1L → H3K79me: modulatory for me1, effectively required for me2/me3
532. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 12112875
     Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer.

     Logan M, Martin JF, Nagy A, Lobe C, Olson EN, Tabin CJ · Genesis 2002
     used by The unnamed osteolineage Cre is Prx1-Cre, which is not osteoblast-restricted - and that changes what the negative result means
533. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11959841
     SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins.

     Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ · Genes Dev 2002
     used by TRIM28 / KAP1 / TIF1beta (Q13263) - the KRAB-ZFP corepressor scaffold in the pan-MLL-fusion core, with the weakest index-fusion p-value but a leukaemic role in another fusion family
534. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11955432
     Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination

     Ma Y, Pannicke U, Schwarz K, Lieber MR · Cell 2002
     used by V(D)J recombination: the immune system deliberately cuts its own chromosomes, using a domesticated transposon
535. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11986204
     Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study.

     Sawyers CL, Hochhaus A, Feldman E, et al. · Blood 2002
     used by Why BCR::ABL1 became treatable — and what KMT2A::AFF1 does not share with it
536. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11526476
     The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation.

     Heppner C, Bilimoria KY, Agarwal SK, Kester M, Whitty LJ, Guru SC, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ, Burns AL · Oncogene 2001
     used by A menin inhibitor may release RELA from menin's restraint — and released RELA is what keeps MLL fusions on chromatin. Prior 0.20, 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, Combine an IKK inhibitor with a clinical menin inhibitor in a KMT2A::AFF1 B-ALL line, and read out fusion OCCUPANCY rather than viability, IKK inhibition and menin inhibition evict the fusion from chromatin by routes that do not share a node, so they should be additive — and the same reasoning predicts that a menin inhibitor alone partially defeats itself. Prior 0.30, Menin represses NF-kB transactivation — through a mapped central region, a SIRT1 cofactor, and an RPA2 off-switch, in every tissue except the one this project cares about, NFKB1 (p105/p50) — the only menin-NF-kB subunit with a co-immunoprecipitation, and the arm the MLL leukaemia data points at, NFKB2 (p100/p52) — menin binds the non-canonical subunit too, and activating that arm SUPPRESSES MLL-AF9 leukaemia, REL (c-Rel) — the third canonical subunit, measured once and found unchanged, and named in zero papers in this disease, RELA (p65) — menin binds it and represses it, and it is required to keep MLL oncoproteins on chromatin
537. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11241789
     Genomic organization, tissue expression, and cellular localization of AF3p21, a fusion partner of MLL in therapy-related leukemia

     Hayakawa A, et al. · Genes, chromosomes & cancer 2001
     used by A partner's 'normal' compartment is usually read off a different tissue, and for at least two KMT2A partners that reading is wrong in blood cells
538. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11423618
     Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification

     Gorre ME, Mohammed M, Ellwood K, et al. · Science 2001
     used by ABL1 — domain architecture and residue coordinates (with the 1a/1b numbering trap), BCR::ABL1 (Philadelphia chromosome), t(9;22)(q34;q11), Mechanism class 3 — constitutive kinase activation (BCR::ABL1, NPM1::ALK, ETV6::NTRK3), Why BCR::ABL1 became treatable — and what KMT2A::AFF1 does not share with it
539. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11463848
     The elongation domain of ELL is dispensable but its ELL-associated factor 1 interaction domain is essential for MLL-ELL-induced leukemogenesis.

     Luo RT, et al. · Mol Cell Biol 2001
     used by AKT and ATM push ELL between two complexes: K355 acetylation sends it to SEC, ATM phosphorylation sends it to LEC, ATM phosphorylates ELL at T551, S561 and S589 - inside the OCEL domain this graph already calls essential for MLL-ELL immortalisation, ELL: the discarded N-terminal EAF-binding site, and a second subtraction the graph had not recorded — the fusion delocalises endogenous EAF1, KMT2A::ELL (MLL-ELL), t(11;19)(q23;p13.1), Not one phosphorylation site has ever been mapped on a KMT2A fusion protein itself - every site in this beat is an inference across the junction, Separation-of-function test: does KMT2A::AFF1 need its C-terminal homology domain to dimerise?
540. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11527155
     Breakpoints of t(4;11) translocations in the human MLL and AF4 genes in ALL patients are preferentially clustered outside of high-affinity matrix attachment regions

     Hensel JP, Gillert E, Fey GH, Marschalek R · Journal of Cellular Biochemistry 2001
     used by Alu repeats and nuclear-matrix anchors in the KMT2A breakpoint region — the genome-feature side of the break, Analysis (runnable): is anything actually enriched at KMT2A breakpoints? The test has never been run against a background that could say no, Hypothesis: KMT2A and AFF1 break where they do because both breakpoint regions are CTCF/cohesin loop anchors sitting in the same nuclear hub, The other half of the break: what is actually known about the AFF1 breakpoint region, and the negative-control gene nobody cites
541. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11389089
     Apoptotic triggers initiate translocations within the MLL gene involving the nonhomologous end joining repair system

     Betti CJ, Villalobos MJ, Diaz MO, Vaughan AT · Cancer Research 2001
     used by Apoptotic nucleases cut KMT2A, and cells that survive the attempt can carry a translocation, Which repair pathway glues the fusion together: classical NHEJ vs alternative end joining
542. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11454856
     Nuclear retention of ATM at sites of DNA double strand breaks.

     Andegeko Y, Moyal L, Mittelman L, Tsarfaty I, Shiloh Y, Rotman G · J Biol Chem 2001
     used by ATM - the DNA-damage kinase that phosphorylates three of the four KMT2A 3' partners
543. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11719380
     Pro-B-cell to pre-B-cell development in B-lineage acute lymphoblastic leukemia expressing the MLL/AF4 fusion protein

     Bertrand FE, Vogtenhuber C, Shah N, LeBien TW · Blood 2001
     used by BLIN-3 (CVCL_QW47) — a three-month-old's KMT2A::AFF1 line used to show the pro-B to pre-B block can be pushed
544. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11301010
     BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function.

     Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S, Wahrer DC, Sgroi DC, Lane WS, Haber DA, Livingston DM · Cell 2001
     used by BRIP1 — downstream effector; rank 22 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
545. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     PDB entries 1H9D (Aml1/cbf-beta/dna complex - 'The Leukemia-Associated AML1 (RUNX1)-CBFbeta Complex Functions as a DNA-Induced Molecular Clamp'), 1E50 (AML1/CBFbeta complex), 1CMO (Runt-domain immunoglobulin motif DNA recognition and heterodimerization - SOLUTION NMR, Runt domain alone, no CBFB and no DNA) and 1IO4 (RUNX1 Runt-CBFbeta heterodimer with C/EBPbeta bZIP on the CSF1R promoter)

     RCSB Protein Data Bank · RCSB PDB 2001
     used by CBFB::MYH11 (CBFbeta-SMMHC), inv(16)(p13;q22), ETV6::RUNX1 (TEL-AML1), t(12;21)(p13;q22)
546. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11282025
     The Cdk9 and cyclin T subunits of TAK/P-TEFb localize to splicing factor-rich nuclear speckle regions.

     Herrmann CH; Mancini MA · J Cell Sci 2001
     used by CCNT1 / cyclin T1 — the regulatory half of P-TEFb, and the one part of the elongation core with any dependency variance
547. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11689614
     Induction of TAK (cyclin T1/P-TEFb) in purified resting CD4(+) T lymphocytes by combination of cytokines.

     Ghose R; Liou LY; Herrmann CH; Rice AP · J Virol 2001
     used by CCNT1 / cyclin T1 — the regulatory half of P-TEFb, and the one part of the elongation core with any dependency variance
548. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11242107
     Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia.

     Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S, et al. · Nat Genet 2001
     used by CEBPA — ranks 25th on the KMT2A scan and sits at the median of random genes
549. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11564775
     Mechanisms of nuclear import and export that control the subcellular localization of class II transactivator.

     Cressman DE, O'Connor WJ, Greer SF, Zhu XS, Ting JP · J Immunol 2001
     used by CIITA - the class II transactivator, a gene menin sits on, and the only antigen-presentation gene in this disease with a knockout that proves the drug acts through it
550. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11350182
     Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community.

     Prip-Buus C, Thuillier L, Abadi N et al · Molecular Genetics and Metabolism 2001
     used by 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
551. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11259575
     MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein.

     Ernst P, Wang J, Huang M, Goodman RH, Korsmeyer SJ · Molecular and Cellular Biology 2001
     used by CREBBP (CBP) — binds the KMT2A transactivation domain, which no fusion keeps, 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: the transactivation domain (aa 2829-2883) and its CBP contact
552. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11579461
     GPHN, a novel partner gene fused to MLL in a leukemia with t(11;14)(q23;q24)

     Eguchi M, et al. · Genes, chromosomes & cancer 2001
     used by Cytoplasmic localisation in KMT2A fusions: the SEPTIN case has an image, the GPHN case has none, and neither partner wins the compartment, KMT2A::GPHN (MLL-gephyrin), t(11;14)(q23;q24) — the 15-residue counterexample
553. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11289145
     t(11;14)(q23;q24) generates an MLL-human gephyrin fusion gene along with a de facto truncated MLL in acute monoblastic leukemia

     Kuwada N, et al. · Cancer research 2001
     used by Cytoplasmic localisation in KMT2A fusions: the SEPTIN case has an image, the GPHN case has none, and neither partner wins the compartment, KMT2A::GPHN (MLL-gephyrin), t(11;14)(q23;q24) — the 15-residue counterexample, Non-elongation KMT2A partners considered and not written: what the searches actually returned, partner by partner, The deferred KMT2A partners: what the counts actually are, what was written, what was rejected, and three numbers the previous enumeration got wrong
554. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11418481
     EAF1, a novel ELL-associated factor that is delocalized by expression of the MLL-ELL fusion protein

     Simone F, Polak PE, Kaberlein JJ, Luo RT, Levitan DA, Thirman MJ · Blood 98(1):201-9 2001
     used by EAF1 — the interactor with an actual subnuclear phenotype: an MLL fusion evicts it from Cajal bodies, and the bodies themselves fall apart, EAF2 (U19) — the EAF paralogue whose ELL-binding domain is a mapped tumour-suppressor module, described entirely in prostate cancer, ELL is in Cajal bodies - or nuclear speckles, depending which paper you read - and the MLL-ELL fusion empties them, ELL: the discarded N-terminal EAF-binding site, and a second subtraction the graph had not recorded — the fusion delocalises endogenous EAF1, KMT2A::ELL (MLL-ELL), t(11;19)(q23;p13.1)
555. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11179008
     Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia.

     Slaugenhaupt SA, Blumenfeld A, et al. · Am J Hum Genet 2001
     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
556. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11483520
     Polymerization of the SAM domain of TEL in leukemogenesis and transcriptional repression

     Kim CA, Phillips ML, Kim W, et al. · The EMBO Journal 2001
     used by ETV6 — domain architecture and residue coordinates, ETV6::NTRK3 (ETV6-TRKC), t(12;15)(p13;q25)
557. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     PDB entry 1JI7: Crystal Structure of TEL SAM Polymer (primary citation: Polymerization of the SAM domain of TEL in leukemogenesis and transcriptional repression)

     RCSB Protein Data Bank; Kim CA et al. · RCSB PDB 2001
     used by ETV6::RUNX1 (TEL-AML1), t(12;21)(p13;q22)
558. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11313922
     Phosphorylation of the EWS IQ domain regulates transcriptional activity of the EWS/ATF1 and EWS/FLI1 fusion proteins

     Olsen RJ, Hinrichs SH · Oncogene 20:1756-64 2001
     used by EWSR1::FLI1 has no residue-resolved, fusion-demonstrated PTM in its retained portion - every mapped site falls past the breakpoint, and the one site shown on the fusion has no residue
559. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11239454
     Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway.

     Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, Grompe M, D'Andrea AD · Mol Cell 2001
     used by FANCD2 — the FA effector menin binds, and the weakest FA gene in this graph's own selectivity scan, FANCF — FA core complex; rank 11 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
560. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11278338
     CD15 expression in mature granulocytes is determined by alpha 1,3-fucosyltransferase IX, but in promyelocytes and monocytes by alpha 1,3-fucosyltransferase IV.

     Nakayama F, Nishihara S, Iwasaki H, Kudo T, Okubo R, Kaneko M, Nakamura M, Karube M, Sasaki K, Narimatsu H · J Biol Chem 2001
     used by FUT9 - the dedicated Lewis-x synthase, structurally solved, and untouched by the KMT2A literature
561. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11448779
     Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1.

     Strahl BD, Briggs SD, Brame CJ, Caldwell JA, et al. · Curr Biol 2001
     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
562. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11387442
     Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor.

     Wang H, Huang ZQ, Xia L, Feng Q, et al. · Science 2001
     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
563. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11509672
     Identification of a signal-responsive nuclear export sequence in class II histone deacetylases.

     McKinsey TA, Zhang CL, Olson EN · Mol Cell Biol 2001
     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, HDAC9 - the only HDAC with a KMT2A-rearrangement expression signature across 211 paediatric patients, and it is high, prognostic, and independent of partner and lineage
564. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11535832
     Cloning and characterization of a histone deacetylase, HDAC9.

     Zhou X, Marks PA, Rifkind RA, Richon VM · Proc Natl Acad Sci U S A 2001
     used by HDAC9 - the only HDAC with a KMT2A-rearrangement expression signature across 211 paediatric patients, and it is high, prognostic, and independent of partner and lineage
565. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11433529
     Human LPP gene is fused to MLL in a secondary acute leukemia with a t(3;11)(q28;q23).

     Dahéron L, Veinstein A, Brizard F, et al. · Genes, Chromosomes & Cancer 2001
     used by HMGA2 (P52926) - a direct KMT2A::AFF1 target through the let-7b axis, and a recurrent fusion partner whose own fusions work by escaping a microRNA rather than by making a chimeric protein, LPP (lipoma-preferred partner) - a KMT2A fusion partner in acute monoblastic leukaemia whose day job is adhesion mechanotransduction, and which is barely expressed in leukocytes
566. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11287972
     Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia

     Druker BJ, Talpaz M, Resta DJ, et al. · New England Journal of Medicine 2001
     used by Imatinib: one molecule, three unrelated rare diseases, twenty years of cross-subsidy, Mechanism class 3 — constitutive kinase activation (BCR::ABL1, NPM1::ALK, ETV6::NTRK3), Why BCR::ABL1 became treatable — and what KMT2A::AFF1 does not share with it
567. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11371647
     Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors

     Koontz JI, Soreng AL, Nucci M, Kuo FC, et al. · Proc Natl Acad Sci U S A 2001
     used by 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
568. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11477655
     t(10;11)-acute leukemias with MLL-AF10 and MLL-ABI1 chimeric transcripts: specific expression patterns of ABI1 gene in leukemia and solid tumor cell lines.

     Shibuya N, Taki T, Mugishima H, et al. · Genes Chromosomes Cancer 2001
     used by KMT2A::ABI1 (MLL-ABI1), t(10;11)(p11.2;q23) — the partner that binds an elongation partner
569. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11713533
     7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes.

     Nguyen VT, Kiss T, Michels AA, Bensaude O · Nature 2001
     used by KMT2A::AFF1 cells run with more free P-TEFb than other leukaemias - and if they do not, this graph's CDK9 story is about recruitment only, Measure the free-versus-7SK-bound P-TEFb split in KMT2A::AFF1 cells - the experiment this whole beat turns on, which has never been done, 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
570. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 12063392
     A novel LPP fusion gene indicates the crucial role of truncated LPP proteins in lipomas and pulmonary chondroid hamartomas.

     Lemke I, Rogalla P, Bullerdiek J · Cytogenetics and Cell Genetics 2001
     used by LPP (lipoma-preferred partner) - a KMT2A fusion partner in acute monoblastic leukaemia whose day job is adhesion mechanotransduction, and which is barely expressed in leukocytes
571. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11157742
     NUP98-HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice

     Kroon E, Thorsteinsdottir U, Mayotte N, Nakamura T, Sauvageau G · EMBO J 2001
     used by NUP98 - the mobile nucleoporin that leaves the pore to put H3K4me3 on haematopoietic promoters, and the shared 5' donor of seven fusions in this graph, NUP98::HOXA9, t(7;11)(p15;p15) — the founding NUP98 fusion, and an incomplete oncogene
572. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11413191
     Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As2O3-induced PML or PML/RARA degradation

     Lallemand-Breitenbach V, Zhu J, Puvion F, Koken M, Honoré N, Doubeikovsky A, Duprez E, Pandolfi PP, Puvion E, Freemont P, de Thé H · Journal of Experimental Medicine 193:1361-71 2001
     used by PML K160 SUMOylation - the retained-portion PTM that became an approved therapy, and the benchmark every other retained site should be measured against
573. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11313484
     Protein interactions of the MLL PHD fingers modulate MLL target gene regulation in human cells.

     Fair K, Anderson M, Bulanova E, Mi H, Tropschug M, Diaz MO · Mol Cell Biol 2001
     used by PPIE (CyP33) — the off-switch the fusion throws away, and the reason PHD3 reinsertion kills transformation
574. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11978968
     Molecular cloning, structure and expression of a novel nuclear RNA-binding cyclophilin-like gene (PPIL4) from human fetal brain.

     Zeng L, Zhou Z, Xu J, Zhao W et al. · Cytogenet Cell Genet 2001
     used by PPIL4 - a spliceosomal cyclophilin whose BioID neighbourhood is the widest overlap with this graph's subject matter of any bait
575. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11073952
     Human chromatid cohesin component hRad21 is phosphorylated in M phase and associated with metaphase centromeres.

     Hoque MT, Ishikawa F · J Biol Chem 2001
     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
576. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11590136
     A potential role for human cohesin in mitotic spindle aster assembly.

     Gregson HC, Schmiesing JA, Kim JS, Kobayashi T, Zhou S, Yokomori K · J Biol Chem 2001
     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
577. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11163245
     Regulation of histone acetylation and transcription by INHAT, a human cellular complex containing the set oncoprotein.

     · Cell 2001
     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
578. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11259672
     The human brm protein is cleaved during apoptosis: the role of cathepsin G.

     Biggs JR, Yang J, Gullberg U, Muchardt C et al. · Proc Natl Acad Sci U S A 2001
     used by SMARCA2 (BRM) - the paralogue nobody measured, and the reason a DepMap rank cannot predict what a BRG1/BRM inhibitor does
579. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11242054
     Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain

     Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T · Nature 2001
     used by 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
580. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11493704
     Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation.

     Lovett BD, Lo Nigro L, Rappaport EF, Blair IA, Osheroff N, Zheng N, et al. · Proc Natl Acad Sci U S A 2001
     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
581. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11336668
     Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency

     Moshous D, Callebaut I, de Chasseval R, Fischer A, de Villartay JP, et al. · Cell 2001
     used by V(D)J recombination: the immune system deliberately cuts its own chromosomes, using a domesticated transposon
582. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11313972
     The ENL moiety of the childhood leukemia-associated MLL-ENL oncoprotein recruits human Polycomb 3.

     Garcia-Cuellar MP, Zilles O, Schreiner SA, et al. · Oncogene 2001
     used by Where KMT2A::MLLT1 actually sits: chromatin occupancy is mapped, subnuclear localisation of the endogenous fusion has never been imaged
583. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11318609
     Transcripts of Fliz1, a nuclear zinc finger protein, are expressed in discrete foci of the murine fetal liver.

     Dahm K, Nielsen PJ, Müller AM · Genomics 2001
     used by ZC3H8 / Fliz1 - the last little-elongation-complex subunit without an entry, discovered in fetal liver haematopoietic progenitors, and a selective BioID2 bait that reaches KMT2A in K562
584. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11448987
     ZNF265--a novel spliceosomal protein able to induce alternative splicing.

     Adams DJ, van der Weyden L, Mayeda A, Stamm S, Morris BJ, Rasko JE · J Cell Biol 2001
     used by ZRANB2 - the only bait in any published proximity experiment that reaches AFF1, AFF4, ELL, MLLT1, CCNT1, KMT2A and DOT1L at once
585. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 10777208
     ENL, the MLL fusion partner in t(11;19), binds to the c-Abl interactor protein 1 (ABI1) that is fused to MLL in t(10;11)+.

     Garcia-Cuellar MP, Schreiner SA, Birke M, et al. · Oncogene 2000
     used by ABI1 (Abl interactor 1 / e3B1) — WAVE-complex cytoskeletal adaptor, KMT2A partner, and an ENL-binding protein, KMT2A::ABI1 (MLL-ABI1), t(10;11)(p11.2;q23) — the partner that binds an elongation partner
586. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 11071626
     The molecular biology of chronic myeloid leukemia

     Deininger MW, Goldman JM, Melo JV · Blood 2000
     used by ABL1 — domain architecture and residue coordinates (with the 1a/1b numbering trap), BCR — domain architecture and residue coordinates
587. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 10988075
     Structural mechanism for STI-571 inhibition of abelson tyrosine kinase

     Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J · Science 2000
     used by BCR::ABL1 (Philadelphia chromosome), t(9;22)(q34;q11)
588. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 10679915
     MLL-CBP fusion transcript in a therapy-related acute myeloid leukemia with the t(11;16)(q23;p13) which developed in an acute lymphoblastic leukemia patient with Fanconi anemia.

     Sugita K, Taki T, et al. · Genes Chromosomes Cancer 2000
     used by BRIP1 — downstream effector; rank 22 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all, Eleven immortalised lines passaged for decades: the competing explanation this beat could not close, FAAP100 — FA core complex; rank 36 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all, FANCA — FA core complex; rank 20 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all, FANCF — FA core complex; rank 11 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all, 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, 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, The FA core complex does not move together, and that is the strongest argument against reading this as a Fanconi-pathway dependency at all, UBE2T — E2; rank 33 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
589. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 10984496
     Energetic and functional contribution of residues in the core binding factor beta (CBFbeta) subunit to heterodimerization with CBFalpha

     Tang YY, Shi J, Zhang L, et al. · Journal of Biological Chemistry 2000
     used by CBFB — domain architecture and residue coordinates
590. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 10914547
     Detection of acute leukemia cells with mixed lineage leukemia (MLL) gene rearrangements by flow cytometry using monoclonal antibody 7.1.

     Wuchter C, ..., Ludwig WD · Leukemia 2000
     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, CSPG4 / NG2 - the flow-cytometry surrogate for a broken KMT2A, and a direct target gene of the fusion that makes it, Step 2: flow cytometry and the CD10-negative pro-B fingerprint
591. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11007474
     Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme

     Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T · Cell 2000
     used by Class switch recombination: a B cell deliberately mutates and cuts its own antibody locus, and the same enzyme causes MYC-IgH translocations
592. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11007475
     Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)

     Revy P, Muto T, Levy Y, Honjo T, Fischer A, Durandy A, et al. · Cell 2000
     used by Class switch recombination: a B cell deliberately mutates and cuts its own antibody locus, and the same enzyme causes MYC-IgH translocations
593. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 10724173
     A clonogenic common myeloid progenitor that gives rise to all myeloid lineages

     Akashi K, Traver D, Miyamoto T, Weissman IL · Nature 2000
     used by Common myeloid progenitor (CMP) — the fork at which KMT2A leukaemia almost always turns one way
594. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 10893273
     CREB-binding protein (CBP)/p300 and RNA polymerase II colocalize in transcriptionally active domains in the nucleus.

     von Mikecz A; Zhang S; Montminy M; Tan EM; Hemmerich P · J Cell Biol 2000
     used by CREBBP (CBP) — binds the KMT2A transactivation domain, which no fusion keeps
595. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 10758153
     Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia.

     Strick R, Strissel PL, Borgers S, Smith SL, Rowley JD · Proc Natl Acad Sci U S A 2000
     used by 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, 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
596. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 11001911
     Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL-AML1 oncoprotein

     Guidez F, Petrie K, Ford AM, Lu H, Bennett CA, MacGregor A, Hannemann J, Ito Y, Ghysdael J, Greaves M, Wiedemann LM, Zelent A · Blood 2000
     used by ETV6::RUNX1 (TEL-AML1), t(12;21)(p13;q22)
597. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 10961856
     Carboxy terminal region of the Fanconi anemia protein, FANCG/XRCC9, is required for functional activity.

     Kuang Y, Garcia-Higuera I, Moran A, Mondoux M, Digweed M, D'Andrea AD · Blood 2000
     used by FANCA — FA core complex; rank 20 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
598. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 11050007
     The fanconi anemia proteins FANCA and FANCG stabilize each other and promote the nuclear accumulation of the Fanconi anemia complex.

     Garcia-Higuera I, Kuang Y, Denham J, D'Andrea AD · Blood 2000
     used by FANCG — FA core complex; rank 27 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
599. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 10706619
     Detection of leukemia-associated MLL-GAS7 translocation early during chemotherapy with DNA topoisomerase II inhibitors.

     Megonigal MD, Cheung NK, Rappaport EF, Nowell PC, Wilson RB, Jones DH, et al. · Proc Natl Acad Sci U S A 2000
     used by GAS7 — growth-arrest-specific F-BAR protein, the second pillar of the forced-oligomerisation model, KMT2A::GAS7 (MLL-GAS7), t(11;17)(q23;p13) — three patients, and the best mouse model in the partner class
600. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 11060035
     The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3.

     Rödel B, Tavassoli K, Karsunky H, Schmidt T, Bachmann M, Schaper F, Heinrich P, Shuai K, Elsässer HP, Möröy T · EMBO J 2000
     used by GFI1 — the repressor that LSD1 inhibitors actually work through, and the scan hit whose literature points the opposite way