KMT2B (MLL2/MLL4) - the other protein menin binds, and the one this graph never wrote

No three-dimensional model is available for this protein, so the map above is the whole picture. That is itself informative: AlphaFold does not model chains this long, and the parts that have been crystallised are held under the entries for the individual domains.

• Every menin inhibitor in this graph engages two menin-KMT2 interfaces, not one. In a normal tissue with no fusion, menin-KMT2A and menin-KMT2B are the ONLY menin-KMT2 interactions present, so the on-target normal-tissue pharmacology of revumenib and its class is KMT2A/B pharmacology by construction.
• The compensation argument runs both ways. If KMT2B buffers loss of KMT2A function, a therapeutic window built on the spared wild-type KMT2A allele is illusory; if it does not, the mouse data saying MLL1 is dispensable remove the pre-bound-wild-type-complex premise that several recruitment arguments in this graph rest on.
• The pharmacodynamic assay cannot see this. There is no validated chromatin readout for KMT2B, so a trial cannot report whether the drug displaced it, and the absence of evidence here is guaranteed by reagents rather than by biology.
• Germline KMT2B loss of function causes early-onset dystonia in children, a neurological phenotype that marrow-focused toxicity monitoring in these trials would not capture. This is a watch item and not a prediction: constitutional haploinsufficiency and partial reversible interface occupancy are different perturbations.
• Menin inhibition paradoxically ACTIVATES bivalent genes, including MHC class I. In a leukaemia being treated in parallel with CD19 or CD22 immunotherapy, raising MHC-I on the blast changes the immune context in a direction nobody has designed for.

1. What is the Kd of menin for the KMT2B N-terminal motif? No co-crystal, no ITC, no SPR and no alanine scan exists. A peptide competition experiment against the known KMT2A MBM1 would take weeks and would tell the field whether a clinical menin inhibitor's IC50 against menin-KMT2B is above or below its therapeutic exposure.
2. Does the Trp7-to-Gly substitution matter? KMT2A W7 sits between the two arginines of RWRFP and is a Gly in KMT2B. If it contributes substantially, menin-KMT2B could be an order of magnitude weaker than menin-KMT2A and the whole shared-target concern shrinks.
3. Can anyone measure KMT2B on chromatin at all? The single technical obstacle named by the field - inadequate chromatin-grade KMT2B reagents - blocks the experiment that would settle this. An endogenous epitope knock-in at the KMT2B locus in an index-fusion line would bypass it entirely and no such line has been reported.
4. Is LEDGF really mainly a KMT2B complex member? One quantitative dataset says so in HeLa and the authors flag the conflict with fragment-based work. If it holds in a t(4;11) blast, this project's LEDGF-IBD targeting argument needs restating.
5. Does KMT2B matter in KMT2A::AFF1 B-lymphoid disease? Every genetic result here is mouse MLL-AF9 myeloid. The infant t(4;11) blast is a fetal-type pro-B cell and the experiment has not been done in one.
6. Why do two CXXC domains with indistinguishable in vitro DNA binding go to different genes in a cell? Whatever supplies that difference is the real address module, and it is not in either protein's CXXC sequence. Nobody has identified it, and it is the most interesting unanswered question this beat met.

1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Label-free quantitative mass spectrometry of GFP-tagged baits across the human SET1/MLL complexes found menin associated with MLL1 and MLL2 (accessions listed by the paper as E9PQG7/Q9UMN6) and not with SET1A/B or MLL3/4, with the authors stating menin binds Mll1 and Mll2 with equal affinity, while PSIP1/LEDGF showed a striking preference for MLL2; PSIP1 was present in only about 25% of menin-MLL1/2 complexes and menin was 4- to 5-fold less abundant than MLL1/2.

   Quantitative dissection and stoichiometry determination of the human SET1/MLL histone methyltransferase complexes. · van Nuland R, Smits AH, Pallaki P, Jansen PW, Vermeulen M, Timmers HT · Mol Cell Biol 2013
   PMID 23508102DOI
   ▸What this evidence cannot show

   Full text read via the PMC HTML route (PMC3647974) on 2026-09-20; Europe PMC fullTextXML returned HTTP 500 and efetch db=pmc returned no body, so routes 2 and 3 of the five-route test failed and route 4 succeeded at 59,051 stripped characters. HeLa cells - an epithelial line with no haematopoietic relevance and no KMT2A fusion. Catalytic subunits were expressed as N-terminal GFP fusions from cDNA, so relative recovery reflects the tagged construct's behaviour. 'Equal affinity' is the authors' wording for equal recovered stoichiometry in a pulldown; no Kd, ITC or SPR was performed on menin-MLL2. The MLL1 bait is accession E9PQG7, a fragment record, not full-length Q03164.

   ▸Evidence that argues against this (1)

   • The authors themselves flag that their LEDGF/MLL2 preference conflicts with an earlier protein-protein interaction study done with fragments of these proteins - the menin-MLL1-LEDGF crystallography line of work, in which the LEDGF contact surface is formed jointly by menin and MLL1. Two methods, two answers, and no adjudication has been published. Huang J et al. 2012
2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Using independent conditional mouse models, endogenous MLL1 was dispensable for MLL-rearranged leukaemia; deletion of the closest paralogue Mll2 alone had a significant impact on survival of MLL-AF9-transformed cells and additional Mll1 loss further reduced viability and proliferation, with MLL1/MLL2 collaboration operating through regulation of distinct pathways rather than redundancy.

   MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia. · Chen Y, Anastassiadis K, Kranz A, et al. · Cancer Cell 2017
   PMID 28609655DOI
   ▸What this evidence cannot show

   Abstract fetched and read 2026-09-20; full text (PMC5598468) not obtained in this beat. Mouse, MLL-AF9, myeloid. Conditional deletion allows compensation over the timescale of the experiment in a way an acute degron would not, so 'Mll1 dispensable' means dispensable in this model over this timescale. No KMT2A::AFF1, no lymphoid disease, no human primary material. The paper's own framing - 'MLL2 as a drug target' - is a proposal, not a demonstrated tractable target, and no KMT2B ligand exists.

   ▸Evidence that argues against this (1)

   • The same senior author's follow-up shows the practical inference does not carry: Mll1;Mll2 co-deletion produces different cellular and molecular consequences from Men1 deletion, and Mll1;Mll2-deficient cells are MORE sensitive to menin inhibitors. A larger wild-type dependency on MLL2 does not make MLL2 the route through which the existing drug class works. Chen Y et al. 2019
3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Whole-genome CRISPR screens coupled to a bivalent MHC class I readout identified Menin-KMT2A/B alongside MTF2-PRC2.1 and PCGF1-PRC1.1 as maintainers of bivalency; genetic loss or pharmacological inhibition of Menin phenocopied polycomb disruption and derepressed bivalent genes; combined KMT2A/KMT2B knockout had the OPPOSITE effect to MEN1 deletion or VTP50469 on IFN-gamma-induced MHC-I; and the authors state that commercially available reagents to monitor KMT2B binding at chromatin are inadequate, so their analyses based only on KMT2A accumulation likely underestimate the consequences of liberating KMT2A/B after Menin loss.

   Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes. · Sparbier CE, Gillespie A, Gomez J, et al. · Nat Cell Biol 2023
   PMID 36635503DOI
   ▸What this evidence cannot show

   Full text read via Europe PMC fullTextXML (PMC7614190) on 2026-09-20, 113,398 stripped characters. The principal system is K-562 (CML, BCR::ABL1) plus pluripotent stem cells - NOT a KMT2A-rearranged line for the bivalency work, so 'pharmacological inhibition of Menin' here is VTP50469 acting on wild-type Menin-KMT2A/B, not on a fusion. The KMT2B reagent limitation is stated by the authors about chromatin-binding reagents specifically; a KMT2B antibody was used for immunoblot (Cell Signaling 63735, clone D6X2E, C-terminal antigen), so the gap is chromatin assays rather than detection in lysate.

   ▸Evidence that argues against this (1)

   • The bivalent-gene derepression is measured in K-562 and pluripotent stem cells. Whether liberating KMT2A/B from active genes happens at all in an infant t(4;11) blast, where the fusion rather than wild-type KMT2A dominates menin occupancy, is untested; a fusion-bearing cell has a competitor for menin that K-562 does not. Chen Y et al. 2019
4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Compounds disrupting the menin-MLL N-terminal interaction also inhibit menin-MLL1 and menin-MLL2 in biochemical and structural assays; nevertheless Men1 deletion in MLL-AF9-transformed cells produces distinct cellular and molecular consequences from Mll1;Mll2 co-deletion, the compounds largely phenocopy menin loss rather than Mll1;Mll2 loss, and Mll1;Mll2-deficient leukaemia cells show ENHANCED sensitivity to menin interaction inhibitors - leading the authors to conclude the predominant action is direct inhibition of the fusion protein without significant contribution from MLL1/MLL2 inhibition.

   Distinct pathways affected by menin versus MLL1/MLL2 in MLL-rearranged acute myeloid leukemia. · Chen Y, Jones KL, Anastassiadis K, et al. · Exp Hematol 2019
   PMID 30315824DOI
   ▸What this evidence cannot show

   Abstract fetched and read 2026-09-20; full text (PMC6472707) not obtained in this beat, so the compound identities, concentrations and the magnitude of the sensitivity shift are not recorded here. Mouse MLL-AF9, myeloid. Genetic co-deletion is chronic and allows adaptation; the enhanced-sensitivity result could reflect a fitness-compromised starting population rather than mechanistic independence. No B-lymphoid or KMT2A::AFF1 arm, and no normal-tissue arm - the question of what the drug does to menin-KMT2A/B in cells with no fusion is not addressed.

   ▸Evidence that argues against this (1)

   • The negative conclusion is about whether the drug WORKS through MLL1/MLL2, not about whether it binds them. The paper concedes the compounds inhibit menin-MLL1 and menin-MLL2, which is the toxicity-relevant fact: in normal tissues where no fusion exists, the only menin-KMT2 interactions available for the drug to hit ARE menin-KMT2A and menin-KMT2B. Sparbier CE et al. 2023
5. E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.review

   KMT2B is a 2,715-amino-acid paralogue of MLL1 that contains a C-terminal SET domain and forms a protein complex with WRAD (WDR5, RBBP5, ASH2L, DPY30), host cell factors 1/2 and Menin, directing H3K4me3 at specific gene promoters and nearby cis-regulatory sites and regulating bivalent developmental genes.

   Structure, Activity and Function of the MLL2 (KMT2B) Protein Lysine Methyltransferase. · Klonou A, Chlamydas S, Piperi C · Life (Basel) 2021
   PMID 34440566DOI
   ▸What this evidence cannot show

   A review, cited only as a map of complex composition and for the fact that its title and stated length (2,715 aa, matching Q9UMN6) disambiguate MLL2 as KMT2B. Abstract read 2026-09-20; full text not obtained. Reviews restate composition without re-measuring it, and this one lists HCF1/2 and Menin without distinguishing which were shown for KMT2B specifically and which are carried over from KMT2A.

   ▸Evidence that argues against this (1)

   • The quantitative AP-MS that measured all six complexes directly found menin substoichiometric - 4- to 5-fold less abundant than MLL1/2 - so 'the MLL2 complex contains Menin' as a flat statement of composition overstates what was measured. Most MLL1/2 complexes do not contain menin at all. van Nuland R et al. 2013
6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   The founding report of the menin-trithorax association states that menin is associated with a histone methyltransferase complex containing two trithorax family proteins, MLL2 and Ash2L, that this complex methylates histone H3 on lysine 4, and that a subset of tumour-derived menin mutants lacks the associated histone methyltransferase activity - but the paper predates KMT2 nomenclature and this entry does not assert which modern gene its 'MLL2' denotes.

   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
   PMID 14992727DOI
   ▸What this evidence cannot show

   **Deliberately unresolved.** The abstract gives no accession and no length; the fetched PubMed record carries no PMCID, so routes 1-4 of the five-route full-text test are unavailable and route 5 (an Elsevier DOI) was not attempted. Because MLL2 has denoted both KMT2B and KMT2D, and because an undecidable naming case is a finding rather than a coin toss, the gene identity here is left open. Any downstream entry that needs this paper to be about KMT2B must first obtain the full text.

   ▸Evidence that argues against this (1)

   • The later quantitative survey of all six human SET1/MLL complexes found menin in the MLL1/2 complexes and explicitly NOT in MLL3/4 - which, if Hughes's MLL2 were KMT2D (an MLL3/4-class enzyme), would be a direct contradiction. That is an argument that Hughes's MLL2 is KMT2B, but it is an argument from a later paper and not a reading of this one. van Nuland R et al. 2013
7. E7established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   UniProt reviewed human records fetched 2026-09-20 give KMT2B as Q9UMN6, 2,715 aa, with synonyms HRX2/KIAA0304/MLL2/MLL4/TRX2/WBP7 and protein name 'Myeloid/lymphoid or mixed-lineage leukemia protein 4', and KMT2D as O14686, 5,537 aa, with synonyms ALR/MLL2/MLL4 and protein name 'Myeloid/lymphoid or mixed-lineage leukemia protein 2'; the KMT2B canonical sequence contains R17-G18-R19-F20-P21-G22-R23-P24, aligning to the KMT2A MBM1 R6-W7-R8-F9-P10-A11-R12-P13 with Phe, the adjacent Pro and the Pro at +3 conserved and Trp7 replaced by Gly, while KMT2C, KMT2D, SETD1A, SETD1B and KMT2E carry no comparable N-terminal motif.

   UniProtKB reviewed human records Q9UMN6 (KMT2B), O14686 (KMT2D), Q8NEZ4 (KMT2C), Q8IZD2 (KMT2E), Q03164 (KMT2A), O15047 (SETD1A), Q9UPS6 (SETD1B) - gene_primary, length and canonical sequence, fetched 2026-09-20 · UniProt Consortium; queries and alignment by this project · Database 2026
   ▸What this evidence cannot show

   The accessions and lengths are database facts and were fetched this session, with only the row whose gene_primary matched the queried symbol retained (rules 62 and 65). **The motif alignment is this project's own and is an inference, not a measurement.** No menin-KMT2B peptide structure, ITC, SPR or alanine scan has been published; conservation of Phe/Pro/Pro is consistent with binding and does not establish affinity, and the Trp-to-Gly change at the position adjacent to the critical Phe could matter a great deal. A sequence argument cannot distinguish a high-affinity motif from a weak one, and this alignment was made by eye rather than by a scored algorithm.

   ▸Evidence that argues against this (1)

   • Sequence conservation of an interaction motif is repeatedly wrong about affinity in this very family: the WDR5 WIN motif is present in KMT2A, KMT2B, SETD1A and SETD1B, and separate co-crystals had to be solved for each because the sequences did not settle the binding chemistry. The same caution applies here with more force, because the KMT2B motif is not even identical. Grembecka J et al. 2010
8. E8established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   MLL binds menin with nanomolar affinity (Kd approximately 10 nM) through two motifs, MBM1 and MBM2, located within the N-terminal 43-amino-acid fragment, with MBM1 the high-affinity motif; alanine scanning of MBM1 identified the hydrophobic residues Phe9, Pro10 and Pro13 as most critical for binding, and MBM1 binds menin in an extended conformation.

   Molecular basis of the mixed lineage leukemia-menin interaction: implications for targeting mixed lineage leukemias. · Grembecka J, Belcher AM, Hartley T, Cierpicki T · J Biol Chem 2010
   PMID 20961854DOI
   ▸What this evidence cannot show

   Abstract fetched and read 2026-09-20. This is a KMT2A study; **KMT2B appears nowhere in it**. It is cited here only to establish which KMT2A residues the alignment in [E7] is anchored to. NMR and peptide competition on an intrinsically disordered fragment, out of the context of the full protein and of chromatin.

   ▸Evidence that argues against this (1)

   • The crystallographic account of the same interface adds a requirement the peptide work cannot see: LEDGF binds a surface formed jointly by menin AND MLL1, so an MBM-only description of menin-KMT2A is incomplete, and by extension a sequence-only argument for menin-KMT2B omits whatever composite surface KMT2B would have to form. Huang J et al. 2012
9. E9moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

   PubMed run 2026-09-20 returns 32 records for `KMT2B AND (leukemia OR leukaemia)` and 4 for `KMT2B AND menin`; PubMed's own query translation maps the string MLL2 to the KMT2D supplementary concept and MLL4 to the KMT2B supplementary concept, so a query written as (KMT2B OR MLL2 OR MLL4) retrieves a KMT2B/KMT2D mixture whose count cannot be attributed to KMT2B.

   NCBI PubMed E-utilities esearch with querytranslation inspected for every count; queries run 2026-09-20 by this project (KMT2B AND menin; KMT2B AND (leukemia OR leukaemia); (MLL2 OR MLL4) AND menin AND (interaction OR binding OR complex)) · NCBI PubMed; queries run by this project · Database 2026
   ▸What this evidence cannot show

   A counted absence is only as good as its symbol set. Aliases HRX2, TRX2, WBP7 and KIAA0304 were not run separately and could add records. All four records from `KMT2B AND menin` were title-checked; none is a menin-KMT2B binding measurement. The complex forms were run separately in this beat (see `concept-kmt2-family-attribution-problem`), and that is what surfaced the decisive paper.

   ▸Evidence that argues against this (1)

   • The decisive KMT2B paper for this entry is unreachable from any KMT2B symbol query: van Nuland 2013 frames everything as 'SET1/MLL complexes' and says MLL2, never KMT2B. A beat that had trusted the 32-record count as the KMT2B literature would have written a confident, bounded and wrong absence - a live instance of rule 64 on this very gene. van Nuland R et al. 2013
10. E10established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    Heterozygous variants in KMT2B (written by these authors as 'also known as MLL4') were reported in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often with a typical facial appearance and characteristic brain MRI findings, with marked clinical benefit including restoration of independent ambulation in some cases following deep brain stimulation.

    Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. · Meyer E, Carss KJ, Rankin J, et al. · Nat Genet 2017
    PMID 27992417DOI
    ▸What this evidence cannot show

    Abstract fetched and read 2026-09-20; full text not obtained (no PMCID in the fetched record). This is germline, constitutional, lifelong haploinsufficiency from conception - it is NOT a safety signal for partial, reversible pharmacological occupancy of a menin-KMT2B interface in an adult or a child, in exactly the way the standing brief says gnomAD constraint is not. It is cited here to name a phenotype worth watching for, not to predict one.

    ▸Evidence that argues against this (1)

    • A developmental phenotype from germline haploinsufficiency systematically overstates the risk of pharmacological interface disruption: the drug does not remove the protein, it removes one of the protein's partners at partial occupancy for weeks, and KMT2B's dystonia phenotype arises from a whole nervous system built without enough of it. Larson JK et al. 2023
11. E11moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    In a cancer-free adult population from gnomAD, pathogenic/likely-pathogenic germline KMT2A-D variants were found at 1:112 (allele frequency 4.46E-03) by manual genomic variant interpretation and 1:832 (6.01E-04) by an automated ACMG pipeline, with ancestry-exclusive variants and higher frequency in males; the authors note that many of these variants are also associated with severe juvenile conditions and that growing evidence supports a role for KMT2B, KMT2C and KMT2D in leukemogenesis.

    KMT2A-D pathogenicity, prevalence, and variation according to a population database. · Larson JK, Hunter-Schlichting DN, Crowgey EL, et al. · Cancer Med 2023
    PMID 36479909DOI
    ▸What this evidence cannot show

    Abstract fetched and read 2026-09-20; full text (PMC10067056) not obtained in this beat, so the per-gene split between KMT2A, B, C and D is not recorded here and the 1:112 figure is for the four genes pooled. A 7.4-fold discrepancy between two interpretation methods on the same data is itself the headline: the prevalence estimate is method-dependent to a degree that makes any single number unusable for counselling. gnomAD is a population sample and 'cancer-free adult' is an ascertainment, not a phenotype.

    ▸Evidence that argues against this (1)

    • Germline burden in a population database says nothing about somatic relevance in this disease. Infant KMT2A-rearranged leukaemia has a famously silent genome, so a predisposition mechanism running through germline KMT2B/C/D variation would have to be demonstrated in infant cohorts, and this paper explicitly leaves that to future research. Meyer E et al. 2017
12. E12strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Fusion proteins built on Mll2, described by the authors as the closest relative of MLL, are INCAPABLE of transforming haematopoietic cells; domain-swap experiments identified the small CxxC zinc-binding region and an adjacent post-CxxC basic stretch as the essential determinants of the difference, and although the combined CxxC/post-CxxC domains of MLL and Mll2 have almost indistinguishable DNA-binding properties in vitro, within cells they guide MLL and Mll2 to a largely non-overlapping target gene repertoire.

    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
    PMID 19060922DOI
    ▸What this evidence cannot show

    Abstract fetched and read 2026-09-20; the fetched record carries no PMCID so full text was not obtained through routes 1-4. **'Mll2' here is KMT2B** - resolved because the authors call it the closest relative of MLL, which the 5,537-aa KMT2D is not. Engineered fusion constructs in murine haematopoietic cells, not a naturally occurring rearrangement; a negative transformation result in one assay system with one set of constructs. The nuclear-localisation and reporter evidence for non-overlapping targets is 2009 methodology and locus-directed rather than genome-wide.

    ▸Evidence that argues against this (1)

    • This is the strongest argument in the literature that KMT2B is NOT interchangeable with KMT2A where it matters most, and it cuts against the shared-menin framing of this entry: menin binds both, but only one of them makes a leukaemogenic fusion, and the determinant is the CXXC/post-CXXC address rather than the menin motif. Any argument that KMT2B substitutes for KMT2A has to explain this result. Chen Y et al. 2017

• ← part ofKMT2B has no haematopoietic cell-state result, and two of the seven records that look like one are about a different gene in muscle

  the bounded cell-state absence for this gene, with the MLL4/MLL2 alias resolutions recorded

• depends on →MHC class I is a bivalent gene set, and a menin inhibitor derepresses it - shown in K-562, SCLC and neuroblastoma, and measured on HLA-A in primary AML, but never once in a KMT2A-rearranged cell

  KMT2B knockout alone modestly impairs MHC-I; dominant at bivalent promoters

• related to →NLRC5 - the MHC class I transactivator, and the route by which interferon activates class I when KMT2A and KMT2B are both gone

  epistasis: KMT2A/KMT2B double knockout makes IFN-gamma-induced class I entirely NLRC5-RFX5-dependent

• ← bindsMEN1 / menin — the adaptor the fusion cannot work without

  menin recovered with MLL1 and MLL2 at equal stoichiometry and with neither SET1A/B nor MLL3/4 (quantitative AP-MS, HeLa)

• related to →KMT2A / MLL1 — the gene that breaks

  closest paralogue; both carry an N-terminal menin-binding motif and no other KMT2 family member does

• binds →PSIP1 / LEDGF p75 — the tether with the best therapeutic index in the whole interactome

  LEDGF/PSIP1 shows a striking preference for the MLL2/KMT2B complex over MLL1/KMT2A in HeLa

• ← inhibitsRevumenib (SNDX-5613, Revuforj) — first approved menin–KMT2A interface inhibitor

  menin-MLL interaction compounds inhibit menin-MLL2 as well as menin-MLL1 and menin-fusion; therapeutic contribution concluded minor in mouse MLL-AF9

• part of →Trithorax against Polycomb at HOXA: the textbook antagonism, and the two ways this disease breaks it

  the complex the screen names is Menin-KMT2A/B; KMT2B's half of it was never measured on chromatin

• analogous to →The menin–KMT2A grip (MBM1), the interface the drugs actually block

  KMT2B F20/P21/P24 align to the KMT2A MBM1 residues F9/P10/P13; alignment only, never measured

• binds →WDR5 — the partner that is not a partner: it binds the half of KMT2A the fusion throws away

  KMT2B carries its own WIN motif competing for the same WDR5 pocket as KMT2A

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

  Mll2 deletion alone impairs MLL-AF9 survival while Mll1 is dispensable - the paralogue is the larger dependency

• related to →SETD1A — a leukemia dependency whose enzyme activity turns out to be dispensable

  SET1/MLL family; SETD1A/B carry WRAD but not menin

• related to →SETD1B - the COMPASS paralogue round 4 deferred for want of a leukaemia paper, which had already been published: its SET domain sets H3K4me3 breadth and MYC in MLL-rearranged AML

  SET1/MLL family; menin is absent from the SET1A/B complexes

• related to →The LEDGF IBD–KMT2A grip: the second half of the clamp, and nobody is drugging it

  LEDGF prefers the KMT2B complex over KMT2A in HeLa - a constraint on the KMT2A-selectivity of an IBD ligand

• ← related toWhen a family shares a complex, the result is family-selective, not member-selective - the protein version of this graph's inhibitor-class rule

  the rule's headline case: 85 entries name a non-KMT2A family member and none of those genes existed

• ← related toMLL2 and MLL4 each name two different genes, and the ambiguity is in the papers, not in the databases

  resolution table: eight instances of MLL2/MLL4 resolve to KMT2B, three to KMT2D, two left open

• ← part ofMenin holds KMT2A and KMT2B, and the graph has been written as if it held one

  the unmeasured half of the Menin-KMT2A/B complex

• ← testsTag endogenous KMT2B in an index-fusion line and measure what revumenib does to it - the experiment the reagents have blocked

  bypasses the stated chromatin-reagent gap that blocks every other route

• related to →CXXC-DNA interface of the KMT2A fusion: a validated but hard target

  KMT2A and KMT2B CXXC domains bind DNA indistinguishably in vitro yet go to non-overlapping genes in cells

• ← related toA quarter of this graph's gene entries have a UniProt localization that nobody measured - and the subnuclear vocabulary UniProt does carry avoids the genes we care about most

  KMT2B's nuclear annotation is experimentally coded but the experiment is nuclear-extract proteomics, not imaging; no subnuclear data exists

• ← related toRe-bound at full text: KMT2B still has no haematopoietic cell-state result - the loose intersection is 1065 records and the tight one 13, and every title read is a review, a complex-membership mention or a congress abstract book

  no full-text record places this protein in a haematopoietic cell state; the recall is its complex's literature

• ← regulatesKMT2A-AKAP8 (AKAP95): graded 'prey-only' by this project, and it is a direct positive modulator of MLL H3K4 methyltransferase activity from a dedicated MLL paper - ADMITTED

  recombinant AKAP95 enhances MLL2-complex H3K4 me1/me2/me3 on recombinant chromatin

• ← regulatesAKAP95 directly enhances H3K4 mono-, di- and tri-methylation - by the KMT2B complex, and ONLY by the KMT2B complex; the paper's own discussion says the MLL1/KMT2A case was never tested

  AKAP95 increases MLL2C H3K4 me1/me2/me3 on recombinant chromatin; the effect is on the enzyme, not the substrate

• ← related toKMT2B has no haematopoietic cell-state result, and two of the seven records that look like one are about a different gene in muscle

  the alias contamination runs both ways and is larger than two of seven: KMT2B's own largest clinical literature is complex early-onset DYSTONIA in 27 individuals, published under 'KMT2B, also known as MLL4' (PMID 27992417), and an eighteen-term cell-state clause does not exclude movement-disorder genetics

• ← bindsTOPBP1 - a real KMT2A contact that no abstract-level query can see, because it is a control panel in a paper about a different protein

  same two-hybrid panel; brief rule 66 ambiguity on 'MLL2 and -4'

• refutes →The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential

  equivalent menin motif, cannot make a transforming fusion - the menin contact is not the determinant