ELL2 — a SEC subunit that almost no cell needs, next to a paralogue almost every cell needs

This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.

• Targeting ELL2 would do nothing: it is dispensable in 99% of cell lines, and the paralogue that matters is the pan-essential one.
• If the ELL slot is filled by ELL1 in B-lineage blasts, then this part of the hijacked machinery has the same no-therapeutic-window problem as the rest of it, and the paralogue asymmetry offers no escape.
• ELL2's documented B-lineage function is secretory differentiation: conditional Ell2 deletion curtails the humoral response and reduces plasma-cell numbers, and the chromatin arm of that phenotype is the H3K4/H3K79 methylation state of the IgH locus. Any agent that interfered with the ELL-family slot would therefore be expected to blunt antibody production - in infants already immunosuppressed by intensive chemotherapy, where infection is a leading cause of treatment-related death.

1. Is ELL1's pan-essentiality a SEC function or something ELL2 cannot substitute for outside SEC? If SEC tolerates either paralogue but only ELL is pan-essential, ELL's essential job is probably not the SEC slot.
2. Which ELL paralogue occupies SEC in KMT2A::AFF1 B-ALL cells specifically? A single immunoprecipitation from SEM cells would answer a question the field has left generic for fifteen years.
3. Does ELL2's near-absence from B lymphocytes (1.7 nTPM) mean the ELL slot in a KMT2A::AFF1 B-ALL blast is filled exclusively by ELL1, and if so does that make the slot pan-essential in exactly the cell type of interest?
4. Is a KMT2A-rearranged pro-B blast ELL3-high and ELL2-low? If it is, then the ELL2 this graph places inside the fusion's SEC is a minority species and several ELL2 claims are weighted wrongly. One RNA-seq comparison against staged normal B progenitors answers it.
5. ELL2 has no fitness effect in any leukaemia line in DepMap and a strong stage-specific function in a cell type this disease never reaches. Is ELL2's presence in the KMT2A::AFF1 complex load-bearing at all, or is it the family member that happens to be around?
6. Does downstream spread of H3K4 and H3K79 methylation distinguish a KMT2A fusion from a normal elongation programme at all? ELL2 knockdown in plasma cells shows that the same two marks extend downstream past an enhancer to the end of the transcribed region in normal B-lineage differentiation with no fusion present. The index fusion's spreading signature is one of this graph's load-bearing chromatin claims, and it has never been compared against a non-fusion elongation-driven spread in the same lineage.
7. Is ELL2's effect on H3K4/H3K79 methylation at IgH separable from its effect on MLL and DOT1L occupancy? Both fall together in the only experiment that exists. A DOT1L-inhibitor arm, or an ELL2 mutant that docks on the scaffold without stimulating elongation, would separate a chromatin function from a recruitment function.
8. Has any histone mark ever been measured under ELL or ELL2 perturbation in a KMT2A-rearranged cell? Not in this tranche. ELL is the fusion partner and the common-essential paralogue; ELL2 is the one with the B-lineage chromatin data. Neither has been assayed for a mark in the disease.

1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   AFF4 is a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, linking transcription elongation to leukemia.

   AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. · Lin C, Smith ER, Takahashi H, Lai KC, Martin-Brown S, Florens L, Washburn MP, Conaway JW, Conaway RC, Shilatifard A · Molecular Cell 2010
   PMID 20159561DOI
   ▸What this evidence cannot show

   This landmark names the ELL family generically in the complex; it does not resolve which ELL paralogue is required in KMT2A-fusion leukemia.

   ▸Evidence that argues against this (1)

   • Complex composition is not requirement. The AEP/SEC papers establish what co-purifies and what a reconstituted complex does; they do not establish that each subunit is rate-limiting in a patient's leukaemia, and this project's own dependency data separates the members by an order of magnitude. Nature 2012
2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   The human PAF complex connects the Super Elongation Complex to RNA polymerase II on chromatin, and ENL-containing and AF9-containing SEC species are distinct complexes.

   Human Polymerase-Associated Factor complex (PAFc) connects the Super Elongation Complex (SEC) to RNA polymerase II on chromatin. · He N, Chan CK, Sobhian B, Chou S, Xue Y, Liu M, Alber T, Benkirane M, Zhou Q · Proceedings of the National Academy of Sciences USA 2011
   PMID 21873227DOI
   ▸What this evidence cannot show

   Biochemistry in non-leukemia systems. The existence of distinct SEC species means complex-membership claims must specify which species.

   ▸Evidence that argues against this (1)

   • ENL-containing and AF9-containing SEC species being distinct complexes is the useful part and it complicates every SEC measurement in this beat: a pulldown or a dependency reports on whichever species dominates in that cell. Nature 2012
3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   ELL2 is not DepMap common-essential (mean Chronos -0.064 across 1,258 lines, -0.051 across leukemia lines, 1.0% of lines depleted) while its paralogue ELL is common-essential at -1.302 with 94.0% of lines depleted; gnomAD gives ELL2 pLI ~1.0 and LOEUF 0.416 with 21 observed against 72.8 expected loss-of-function variants; HPA gives liver 81.0, bone marrow 45.6, classical monocyte 0.8 and naive B cell 1.7 nTPM.

   DepMap CRISPR (Chronos) gene effect via the Open Targets Platform GraphQL API; gnomAD v4 constraint via the gnomAD GraphQL API; Human Protein Atlas consensus tissue nTPM via the HPA API · Broad Institute DepMap; gnomAD; Human Protein Atlas; Open Targets Platform · Databases 2026
   ▸What this evidence cannot show

   DepMap release version not stated by the API. A gene expressed in few of the screened lines will score as non-essential regardless of its biology, and ELL2's narrow expression makes this a live alternative explanation for the paralogue asymmetry.

   ▸Evidence that argues against this (1)

   • The near-zero DepMap score is not evidence that ELL2 loss is harmless, because the assay cannot see the phenotype that matters. B-cell-conditional Ell2 deletion curtails the humoral response, reduces plasma-cell numbers and impairs immunoglobulin secretory-specific mRNA production and the unfolded protein response. Cell-line CRISPR panels measure proliferation, not antibody secretion, so 1.0% of lines depleted says nothing about the immune cost of ELL2 blockade in a child already immunosuppressed by leukemia therapy. The low score and the real toxicity are not in conflict; they are measurements of different things, and the entry should not read the first as reassurance about the second. Park KS et al. 2014
4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   The ELL2 occludin-homology domain binds an AFF4 peptide, resolved crystallographically at 2.00 A (5JW9); ELL2's N-terminal ELL_N2 domain has an NMR structure (2E5N); and ELL2 is resolved within an active Pol II-DSIF-ELL2-EAF1 elongation complex at 3.3 A (7OKX).

   RCSB PDB entries 5JW9, 2E5N and 7OKX, verified against the RCSB data API for title, experimental method and resolution · RCSB Protein Data Bank · RCSB PDB 2026
   ▸What this evidence cannot show

   5JW9 resolves an ELL2-AFF4 contact, not an ELL2-AFF1 contact; AFF1 is the fusion partner in KMT2A::AFF1 and the two scaffolds are paralogues, not the same protein.

   ▸Evidence that argues against this (1)

   • Counting PDB entries measures how tractable a protein was to CRYSTALLISE, which correlates with being small, ordered and well-behaved rather than with being druggable. What decides design value is whether the deposited density covers the site that matters, at a resolution that supports modelling, in the relevant state — and this graph has repeatedly found structures described in the direction that overstates what is resolved. A 2.00 A occludin-homology domain with an AFF4 peptide is a good structure of one contact; the NMR N-terminal domain and the cryo-EM placement are separate fragments with nothing joining them. RCSB PDB 2026
5. E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   No primary study was found showing that ELL2 specifically, rather than an ELL-family protein generically, is the required paralogue in KMT2A-fusion leukemia.

   PubMed search for ELL2 paralogue specificity in KMT2A/MLL-fusion leukemia, conducted for this graph on 2026-09-18; no such study retrieved · Oncofusion Knowledge Graph project, using the NCBI PubMed E-utilities · Literature search 2026
   ▸What this evidence cannot show

   Bounded by query terms and indexing; not proof of absence.

   ▸Evidence that argues against this (1)

   • Searched again and the gap is confirmed, but it should be stated more strongly than 'no primary study was found'. Targeted searches for ELL2-specific work in KMT2A-fusion leukemia returned nothing, while the paralogue ELL is DepMap common-essential at -1.302 with 94.0% of lines depleted and ELL2 sits at -0.064 with 1.0%. The straightforward reading is not that ELL2 is untested, it is that ELL2 is the dispensable paralogue and ELL is the required one, and that a SEC-directed strategy aimed at ELL2 is aimed at the member of the pair that cells do not need. Nothing in the literature contradicts that reading. Broad Institute DepMap; Open Targets Platform; search performed by this project 2026
6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

   Across 54 DepMap leukemia lines ELL2 correlates with MEN1 at r = 0.096, confidence interval -0.223 to 0.391, crossing zero.

   Leukemia-restricted co-dependency with MEN1, bootstrap and permutation testing; analyses/wrad-discrimination/ in this project · Broad Institute DepMap; Open Targets Platform; analysis run by this project · Database and derived analysis 2026
   ▸What this evidence cannot show

   Our own computation in 54 lines. A gene with almost no dependency variance across the panel cannot produce a meaningful correlation, so this null is uninformative.

   ▸Evidence that argues against this (1)

   • A correlation of 0.096 with an interval crossing zero is a null result. Oncofusion knowledge graph (internal analysis) 2026
7. E7strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   B-cell-conditional Ell2 deletion curtails the humoral response, reduces plasma-cell numbers and impairs immunoglobulin secretory-specific mRNA processing and the unfolded protein response.

   Transcription elongation factor ELL2 drives Ig secretory-specific mRNA production and the unfolded protein response. · Park KS, Bayles I, Szlachta-McGinn A, Paul J, Boiko J, Santos P, Liu J, Wang Z, Borghesi L, Milcarek C · Journal of Immunology 2014
   PMID 25238757DOI
   ▸What this evidence cannot show

   B-cell conditional knockout addressing plasma-cell differentiation and immunoglobulin secretion, not leukemia. The phenotype is in terminal B differentiation, not in the progenitor compartment KMT2A::AFF1 arises from.

   ▸Evidence that argues against this (1)

   • This is a mouse knockout describing what the gene does in normal development or normal haematopoiesis, over the animal's whole life, with the protein entirely absent. A drug gives partial reversible inhibition in an adult for weeks. The experiment bounds the biological requirement and not the therapeutic window. Curtailed humoral response and impaired plasma-cell function is a manageable toxicity in a population already receiving immunoglobulin replacement after CD19-directed therapy, so the example is less prohibitive than it reads. Journal of Clinical Oncology 2025
8. E_ecas_watch_verdictmoderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   ELL2 is a named subunit of ECAS, a promoter-proximal assembly joining an AFF4-ELL2-EAF1 elongation module to a U2 snRNP-associated intron binding complex and reported as molecularly distinct from canonical P-TEFb-containing SEC. This does NOT satisfy the reopening condition recorded for ELL2 in this graph - 'an ELL2-specific requirement in KMT2A-fusion leukemia is reported' - because the MLL-rearranged leukaemia dependency demonstrated is AQR's, not ELL2's. ELL2's strike therefore stands, checked 2026-09-19.

   A dual-module ECAS complex couples transcription elongation and RNA processing · Xiang Y, Wang H, Yin Z, et al. (Liang K, senior author) · Molecular Cell, online ahead of print 16 September 2026 2026
   PMID 42748909DOI
   ▸What this evidence cannot show

   Read as abstract only; online ahead of print. The leukaemia phenotype is reported in MOUSE haematopoietic cells and described as 'MLL-rearranged' without the abstract naming the fusion partner, the model, or whether any human KMT2A::AFF1 material was used. 'Profoundly impairs' is the authors' wording and is not quantified in the abstract. Acute perturbation of a spliceosomal RNA helicase has wide consequences, so a leukaemia-selective window is not established by these data. Recorded as a watch verdict by the coordinator: the paper was surfaced by scripts/watch-reopening-conditions.py and read specifically against ELL2's stated reopening condition.

   ▸Evidence that argues against this (1)

   • The verdict is narrow and could be wrong in spirit. If ECAS is genuinely distinct from SEC, then ELL2's previous assessment was made against the wrong complex, and a requirement demonstrated for the ECAS module could be an ELL2 requirement that nobody has yet separated from AQR's. The condition as written asks for an ELL2-SPECIFIC result, which keeps the strike in place, but the ground the strike was made on has shifted and the condition may now be the wrong test. Xiang Y et al. 2026
9. E9moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   ELL2's nuclear accumulation is carried by a strong bipartite nuclear localisation signal at residues 311-338 within the conserved region R1: confocal microscopy of an ELL2 truncation series shows R1 is decisive for nuclear localisation, K319, R320 and K333/K334 are each required, and the isolated ELL2 NLS is sufficient to translocate an unrelated reporter into the nucleus.

   Identification of a Nuclear Localization Signal (NLS) in Human Transcription Elongation Factor ELL2. · Kohrt S, Baheerathan A, Prokscha J, Zwosta A, Sticht H, Thoma-Kress AK · Cell Biochem Funct 2024
   PMID 39582094DOI
   ▸What this evidence cannot show

   Transfected, epitope-tagged truncation constructs in a non-haematopoietic line; the endogenous protein is not imaged. The starting point was an in silico prediction that the experiments then confirmed, which is the correct order but means the residue set tested was prediction-directed rather than unbiased. Nothing here addresses subnuclear position, and nothing addresses ELL2 in leukaemia.

   ▸Evidence that argues against this (1)

   • A localisation determinant mapped by overexpression may not be what sets the endogenous distribution, because ELL2's abundance is controlled by degradation rather than by import: the Siah1 ubiquitin ligase targets ELL2 and host factors that antagonise Siah1 substrate binding stabilise it. In a cell where ELL2 protein level is set by a ubiquitin ligase, a transfected excess of tagged ELL2 saturates that control and reports the import machinery's capacity rather than the endogenous steady state. Wu J et al. 2020
10. E10established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    ELL2's documented cell-type-specific function is in the plasma cell, not in any leukaemic or progenitor cell: it is induced in plasma cells and directs immunoglobulin secretion by enhancing proximal poly(A) site use and terminal secretory-exon skipping in the heavy-chain pre-mRNA, with ELL2 and CstF-64 loading together onto RNA polymerase II across the Igh locus.

    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
    PMID 19749764DOI
    ▸What this evidence cannot show

    B-cell and plasma-cell systems with siRNA, hnRNP F transfection and reporter constructs. Not leukaemia, not KMT2A-rearranged, and not an identity-maintenance experiment - the readout is the secretory-form mRNA, which is an output of the cell, not what the cell is. Read: abstract only.

    ▸Evidence that argues against this (1)

    • The B lineage runs a paralogue split that this claim does not capture: ELL3 is selectively expressed in B cells prior to ELL2 and drives proliferation and survival there. So 'ELL2 is the B-lineage elongation factor' is wrong, and a KMT2A-rearranged pro-B blast sits developmentally on the ELL3 side of the handover, not the ELL2 side - which nobody has measured. Alexander LMM et al. 2017
11. E11moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    ELL3 is selectively expressed in B cells prior to ELL2 and drives proliferation and survival at that earlier B-cell stage, so the ELL family is split by developmental position within the B lineage.

    Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival. · Alexander LMM, Watters J, Reusch JA, Maurin M, Nepon-Sixt BS, Vrzalikova K, Alexandrow MG, Murray PG, Wright KL · Mol Immunol 2017
    PMID 28858629DOI
    ▸What this evidence cannot show

    B cells and B-cell lines; no KMT2A-rearranged arm and no measurement in a pro-B blast, which is the stage the index disease occupies. Read: abstract only.

    ▸Evidence that argues against this (1)

    • A stage-wise expression split does not establish that the two factors are functionally distinct inside the SEC, and no double-depletion experiment separating ELL2 from ELL3 in one cell was found; the plasma-cell ELL2 phenotype was obtained in cells that express other family members. Martincic K et al. 2009
12. E12strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    ELL2 IS REQUIRED FOR TWO HISTONE MARKS AND FOR MLL/DOT1L OCCUPANCY AT A B-LINEAGE LOCUS: in plasma cells, siRNA reduction of ELL2 reduced processing to the secretion-specific poly(A) site and also influenced the methylations of histone H3K4 and H3K79 on the IgH gene, impacted P-TEFb, Ser-2 carboxy-terminal phosphorylation and polyadenylation-factor additions to RNA polymerase II, and impaired the associations of MLL and Dot1L with the IgH gene; ChIP on cultured mouse B and plasma cells bearing the identical IgH gamma-2a gene showed that in plasma cells H3K4 and H3K79 methylation extended farther downstream, past the IgH enhancer to the end of the transcribed region.

    The eleven-nineteen lysine-rich leukemia gene (ELL2) influences the histone H3 protein modifications accompanying the shift to secretory immunoglobulin heavy chain mRNA production. · Milcarek C, Albring M, Langer C, et al. · J Biol Chem 2011
    PMID 21832080DOI
    ▸What this evidence cannot show

    Abstract read from the eutils record; full text not read in this tranche. MOUSE B and plasma cells in a normal secretory-differentiation programme - NOT leukaemia, NOT a KMT2A fusion, and the MLL referred to is wild-type MLL1, so rule 73 applies and nothing here is index-fusion evidence. siRNA knockdown, with the usual incompleteness. The experiment does NOT separate an effect of ELL2 on the marks from an effect on the occupancy of the enzymes that deposit them, because both fall together; 'ELL2 is required for H3K79 methylation' and 'ELL2 is required for DOT1L to be at IgH' are one observation here. 'Influenced the methylations' is the abstract's own hedged wording and the direction and magnitude per mark cannot be graded from it. Not cited anywhere in this corpus before 2026-09-21, verified with scripts/check-citation-reuse.py.

    ▸Evidence that argues against this (1)

    • This result is best read as a CONTROL against, rather than support for, the corpus's spreading argument, and that is why it is recorded here rather than folded into the fusion story. MLL-AF4 spreading into gene bodies with increased H3K79me2/3, disrupted H3K36me3 and unmethylated CpG is treated in this graph as a fusion-associated chromatin signature that governs DOT1L-inhibitor sensitivity. The IgH result shows downstream extension of the same two marks in a NORMAL B-lineage differentiation programme with no fusion present, driven by an ELL-family elongation factor. Downstream spread of H3K4 and H3K79 methylation is therefore not diagnostic of a fusion, and any entry inferring fusion activity from spread alone is under-determined. Kerry J et al. 2017
13. E13moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    A HISTONE DEACETYLASE SITS UPSTREAM OF ELL2 RECRUITMENT: SIRT6 binds RNA polymerase II and prevents release of the negative elongation factor NELF, stabilising promoter-proximal pausing; genetic depletion of SIRT6, or its chromatin deficiency on glucose deprivation, causes intragenic enrichment of acetylated histone H3 at lysines 9 and 56 (H3K9ac, H3K56ac), activation of CDK9 which phosphorylates NELF and the Pol II C-terminal domain, and enrichment of MYC, BRD4, PAF1 and the super elongation factors AFF4 and ELL2, increasing expression of genes in metabolism, protein synthesis and embryonic development.

    The Histone Deacetylase SIRT6 Restrains Transcription Elongation via Promoter-Proximal Pausing. · Etchegaray JP, Zhong L, Li C, et al. · Mol Cell 2019
    PMID 31399344DOI
    ▸What this evidence cannot show

    Abstract read from the eutils record; already cited once in this corpus (mechanism-pcaf-af9-k339-camkii-hdac5-oligomer-switch) for a different purpose. NOT leukaemia and NOT a KMT2A-fusion system; the perturbations are SIRT6 depletion and glucose deprivation, the latter a broad metabolic stress. ELL2 appears as one of several factors whose enrichment increases, alongside AFF4, MYC, BRD4 and PAF1, so nothing here is ELL2-specific mechanism - it is ELL2 as a member of a recruited set. Note the factor names: AFF4 and ELL2, not AFF1 and ELL, so this cannot be read across to the fusion's own scaffold without test.

    ▸Evidence that argues against this (1)

    • The recruitment of 'super elongation factors' as a set understates a distinction this graph already records: SEC is not one complex. The PAF-complex work establishes that ENL-containing and AF9-containing SEC species are distinct assemblies, and this entry separately records ELL2 as a subunit of ECAS, an AFF4-ELL2-EAF1 module reported as molecularly distinct from canonical P-TEFb-containing SEC. So 'AFF4 and ELL2 are enriched after SIRT6 loss' does not identify which assembly was enriched, and the inference that an eraser's removal feeds the fusion's own elongation route is unsupported. He N et al. 2011

• ← related toELL2 — domain architecture and residue coordinates

  residue-level domain coordinates for ELL2 (UniProt O00472, 640 aa)

• ← part ofCCNT1 / cyclin T1 — the regulatory half of P-TEFb, and the one part of the elongation core with any dependency variance

  Counter-evidence: both are SEC components whose druggability case is weak — P-TEFb inhibition in AML produced excess treatment-related deaths, and ELL2 is the dispensable paralogue

• binds →AFF4 — the textbook SEC scaffold that KMT2A::AFF1 cells need LESS than other leukemias

  OCEL domain binds the AFF4 scaffold; crystal structure 5JW9 at 2.0 A

• part of →Step 3 — The hijack: the fusion drags the super elongation complex to paused RNA polymerase II

  ELL-family slot of the Super Elongation Complex

• related to →ELL — rank 7 on selectivity and the deepest common-essential in the top ten, with one NMR fragment to its name

  paralogue asymmetry: ELL pan-essential (94% of lines), ELL2 dispensable (1%)

• part of →The ELL/EAF activation module (ELL2, EAF1, EAF2) — a general elongation stimulator, not a KMT2A-fusion dependency

  ELL2-EAF1 is resolved in an active Pol II elongation complex (7OKX)

• ← related toELL3 — the third ELL paralogue, which marks enhancers and recruits SEC rather than sitting inside it

  completes the ELL family; the 'three interchangeable paralogues' framing is not established for ELL3

• ← refutesThe little elongation complex (ELL + ICE1 + ICE2 + ZC3H8) — the other place ELL works, and why ELL's pan-essentiality is probably not about the fusion

  offers a mechanistic answer to the ELL/ELL2 paralogue asymmetry that entry left open

• ← bindsEAF1 — the interactor with an actual subnuclear phenotype: an MLL fusion evicts it from Cajal bodies, and the bodies themselves fall apart

  EAF1 aa 1-268 modelled with ELL2 aa 1-640 on Pol II in PDB 7OKX (3.3 A composite)

• ← bindsThe ELLbow: AFF4 301-351 wrapped over the ELL2 occludin domain at 2.0 A, Kd 86 nM - and no structure of ELL itself, the partner in t(11;19)

  ELL2 occludin domain ~519-640

• ← part ofAQR (Aquarius) - a spliceosomal RNA helicase whose loss impairs MLL-rearranged leukaemia stem cells

  AQR and ELL2 are both subunits of ECAS, a promoter-proximal assembly reported as molecularly distinct from canonical P-TEFb-containing SEC (PMID 42748909).

• ← related toAFF1 / AF4 — the 3' half of the fusion, and a target with almost no structural footing

  Same ECAS finding (PMID 42748909) links the AFF1/AFF4 complex-identity problem to this graph's ELL2 entry, where the ECAS composition was already logged.

• ← related toPhosphosite counts for the five 3' partners: the atlas beats UniProt 1.4-6.0x, and the retained/lost split is completely different for each partner

  7 observed sites; paralogue control, not a KMT2A partner

• ← depends onHEXIM1 - 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

  ELL2 is required for the P-TEFb-release-driven induction of HEXIM1

• ← related toSEC-L2 — the AFF2-scaffolded super-elongation-like complex: P-TEFb plus ENL and AF9, and NO ELL

  ELL2 was looked for in SEC-L2 by MudPIT and endogenous co-IP and NOT found

• related to →ELL is in Cajal bodies - or nuclear speckles, depending which paper you read - and the MLL-ELL fusion empties them

  ELL has a subnuclear literature and ELL2 has none; the paralogues are treated as interchangeable and have not been compared on this axis

• expressed in →Plasma cell - the end of the B lineage, and the only cell type in which ELL2 has a documented job

  ELL2 is induced on plasma-cell differentiation and directs the membrane-to-secreted switch of immunoglobulin heavy-chain mRNA; expressed_in plus required_in for that output, NOT identity maintenance, and no KMT2A-rearranged arm

• regulates →H3K79me2 - the di-methyl state the leukaemia actually runs on, and the one menin turns out to govern only half of

  REQUIRED FOR, AND FOR THE ENZYME'S PRESENCE: ELL2 knockdown in plasma cells alters H3K4 and H3K79 methylation on the IgH gene AND impairs MLL and Dot1L association there; in plasma cells both marks extend downstream past the IgH enhancer to the end of the transcribed region. Mouse B-lineage, NO fusion present - so this is a CONTROL for the fusion spreading signature, not an example of it.

• regulates →H3K4me3 - the mark KMT2A's own SET domain writes, that the fusion cannot write, that an interface in this graph already binds, and that switches PRC2 off

  Same experiment, same limit: ELL2 knockdown influences H3K4 methylation on the IgH gene and the mark extends downstream in plasma cells. The abstract says 'methylations of histone H3K4' without specifying the methylation state, so me1/me2/me3 is not resolved here.

• related to →DOT1L — the target where excellent chemistry met an indirect interaction

  ELL2 is required for DOT1L OCCUPANCY at a locus: Dot1L association with the IgH gene is impaired in the absence of ELL2, in mouse plasma cells. The experiment does not separate this from ELL2's effect on the marks themselves.

• ← related toELL — rank 7 on selectivity and the deepest common-essential in the top ten, with one NMR fragment to its name

  PARALOGUE CONTRAST EXTENDED TO CHROMATIN, AND IT INVERTS: ELL has the dependency (common-essential, -1.302, 94% of lines) and the fusion; ELL2 has the structures and the ONLY locus-level H3K4/H3K79 data in the family (IgH, mouse B and plasma cells). Nobody has measured a mark for ELL.

• ← testsAuditing the seven strikes before applying them: nine of ten decisions stand, four for different reasons than were given, and one clinical argument fails

  strike confirmed with reasoning inverted: the cited paper shows ELL2 is not dispensable

• ← supportsThe dependencies this project keeps failing to see are the buffered ones: paralogue redundancy and guide placement, not absence of biology

  applied to ELL/ELL2 the hypothesis predicts the observed split, which is non-redundancy, so it supports rather than undermines the ELL2 strike

• ← related toThe bite-back of striking a target: a wrong strike costs a cure and generates no data that it was wrong

  the cost here is the word 'dispensable', which would license treating ELL2 blockade as low-risk against a published humoral-failure phenotype