ZMYND11 (BS69) - an H3.3K36me3 reader that restrains elongation, is itself the 5' partner of a chromatin-hijacking AML fusion driving HOXA/MEIS1/MYB, and whose promoter is the third-strongest MLL1-N bin in RS4;11

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.

• ZMYND11 is a tumour suppressor whose low expression correlates with worse outcome in breast cancer and whose germline loss causes a syndromic intellectual disability. Any intervention that reduces ZMYND11 function - including, if the preprint holds, anything that mimics loss of its restraint on KMT2A - carries a neurodevelopmental liability in a paediatric population and a general growth-promoting liability.
• If ZMYND11 restrains KMT2A, then ZMYND11 loss is a candidate mechanism for menin-inhibitor-independent fusion activity, and it would be invisible to every assay this project currently reasons about: it is a change in a brake, not in the fusion, and it would not show as resistance in a menin-binding assay or as a MEN1 mutation.
• The ZMYND11::MBTD1 precedent shows what happens when this protein's PWWP module is repurposed rather than lost. A therapeutic PWWP-blocking chemical developed against that fusion would also block wild-type ZMYND11's tumour-suppressive elongation brake in every other cell, which is the essential-function version of the same target.

1. Should this graph hold a fusion-zmynd11-mbtd1 entry and an analogy entry beside it? A PWWP reader welded to NuA4/TIP60, producing HOXA/MEIS1/MYB/MYC and answering to a downstream epigenetic drug, is the KMT2A-fusion mechanism assembled from different parts, and the graph's analogy set does not contain it.
2. Does ZMYND11 bind KMT2A through a region retained in KMT2A::AFF1? If the 2025 preprint's interaction maps to the N-terminal portion that fusions keep, then ZMYND11 is a candidate brake on the fusion itself and its loss would be a candidate resistance or aggressiveness mechanism. If it maps to the SET-containing C-terminus, the fusion is blind to it and the finding is irrelevant here. The abstract does not say which.
3. What does the RS4;11 input track read at chr10:180,000? A 183.0x enrichment at the extreme 5' end of chromosome 10 needs its input value before it is quoted again, and the file is already on disk.
4. ZMYND11 reads H3K36me3 only on H3.3, and this graph holds mark-h3k36me2-3 with no variant distinction. Does any entry in this corpus that reasons about H3K36me3 - including interface-psip1-pwwp-h3k36me-nucleosome - depend on which histone variant carries the mark?
5. Wild-type ZMYND11 restrains elongation and KMT2A::AFF1's core activity IS elongation. Is ZMYND11 expression or occupancy altered in KMT2A-rearranged blasts relative to normal pro-B cells? Nothing measures this, and it is answerable from existing expression compendia.

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

   ZMYND11 is Q15326 (ZMY11_HUMAN), 602 aa, with synonyms BS69 and BRAM1; its feature table gives a SAMD1-like winged-helix domain at 6-82, a PHD-type zinc finger at 100-148, a bromodomain at 149-255, a PWWP domain at 280-331, a MYND-type zinc finger at 563-598, a nuclear localisation signal at 394-400 and an adenovirus-E1A interaction region at 452-572; it is localised to nucleus and chromosome, is ubiquitously expressed, specifically recognises H3.3K36me3 and not H3.1 or H3.2, functions as a transcription corepressor by modulating RNA polymerase II at elongation, and acts as a tumour suppressor.

   UniProtKB Q15326 (ZMY11_HUMAN), Zinc finger MYND domain-containing protein 11 · UniProt Consortium · UniProt 2026
   ▸What this evidence cannot show

   Fetched live 2026-09-23 via gene_exact:ZMYND11 AND organism_id:9606 AND reviewed:true, which returned exactly ONE reviewed record, so rule 62 does not fire. data/symbol-collisions.json (208 rows) word-boundary grepped for ZMYND11 before the first query: no row - but BS69 is a short alias token and is not in the registry either, and BS69[tiab] returns only 41 records so the alias arm is small. The H3.1/H3.2 non-binding statement carries UniProt's 'By similarity' flag, i.e. it is inferred rather than experimentally annotated on the human protein; the human experiment is E3. Per rule 91, the papers UniProt cites for the localisation comment were not opened.

   ▸Evidence that argues against this (1)

   • UniProt's own DISEASE section lists ZMYND11 in autosomal-dominant intellectual developmental disorder 30 with speech delay and behavioural abnormalities, and nothing about leukaemia. The database view of this gene is a neurodevelopmental tumour suppressor; the leukaemia biology that makes it interesting here - a recurrent fusion partner driving HOXA/MEIS1 - is not represented in the record at all. Nat Commun 2021
2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   HGNC assigns ZMYND11 (HGNC:16966, 'zinc finger MYND-type containing 11') the primary Ensembl gene id ENSG00000015171, cytoband 10p15.3 and UniProt Q15326, with alias symbols BS69 and BRAM1 and no previous symbol; Ensembl places the gene at GRCh37 chr10:180,405-300,577 and GRCh38 chr10:130,088-254,771, both on the plus strand.

   HGNC record HGNC:16966 (ZMYND11) and Ensembl gene ENSG00000015171 on GRCh37 and GRCh38 · HUGO Gene Nomenclature Committee; Ensembl · genenames.org / Ensembl 2026
   ▸What this evidence cannot show

   Fetched live 2026-09-23 and resolved into a note before any sentence using them was written. No previous official symbol, so rule 69 does not apply; the alias BS69 was nonetheless run as a separate literature arm (E9) because it is the name most of the pre-2014 biochemistry uses.

   ▸Evidence that argues against this (1)

   • The GRCh37 and GRCh38 spans for ZMYND11 differ by ~50 kb in start coordinate (180,405 versus 130,088), which is larger than the distance from the Q118 bin to the gene. Any statement in this entry that mixes the two builds would be wrong by more than the effect being described, so both spans are carried explicitly and the bin arithmetic is done only in GRCh37, the build the deposited data uses. Ensembl 2026
3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   ZMYND11 specifically recognises H3K36me3 on the histone variant H3.3; trimethyl-lysine is bound in an aromatic cage within the PWWP domain, and H3.3-specificity is achieved by encapsulation of the H3.3-specific Ser31 residue in a composite pocket formed by the tandem bromo-PWWP domains. ZMYND11 co-localises genome-wide with H3K36me3 and H3.3 in gene bodies, its occupancy requires pre-deposited H3.3K36me3, and although associated with highly expressed genes it acts as an unconventional transcription co-repressor by modulating RNA polymerase II at the elongation stage; it represses a transcriptional programme essential for tumour-cell growth, low ZMYND11 correlates with worse prognosis in breast cancer, and ZMYND11 overexpression suppresses cancer cell growth in vitro and tumour formation in mice.

   ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression · Wen H, Li Y, Xi Y, Jiang S, Stratton S, Peng D, et al. · Nature 2014
   PMID 24590075DOI
   ▸What this evidence cannot show

   Abstract-level read; the full text was not opened this session, so the cell lines used and the exact residue boundaries of the composite Ser31 pocket are not recorded here. The tumour-suppressor and prognostic claims are made in breast cancer, not leukaemia. This is the founding reader paper and is cited for the chemistry and the elongation role, not for anything haematopoietic.

   ▸Evidence that argues against this (1)

   • A second 2014 paper places the same H3.3K36me3 recognition upstream of regulated pre-mRNA PROCESSING rather than only of polymerase elongation rate, so 'ZMYND11 slows Pol II' is one reading of a module whose documented output includes splicing. A ChIP-based elongation model and an RNA-processing model are not distinguishable from occupancy data alone. Mol Cell 2014
4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   The recurrent t(10;17)(p15;q21) creates the ZMYND11-MBTD1 fusion in a subset of AML; the fusion confers indefinite self-renewal on primary murine haematopoietic stem/progenitor cells ex vivo and causes AML in vivo; it directly binds and maintains high expression of Hoxa, Meis1, Myb, Myc and Sox4; it recruits the NuA4/TIP60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks; systematic mutagenesis shows that both the TIP60 interaction and an intact H3K36me3-binding PWWP domain are essential for oncogenesis; and bromodomain inhibition acting downstream is efficacious in treating ZMYND11-MBTD1-induced AML.

   ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism · Li J, Galbo PM, Gong W, Storey AJ, Tsai YH, Yu X, et al. · Nat Commun 2021
   PMID 33594072DOI
   ▸What this evidence cannot show

   Abstract-level read; the full text was not opened this session. The functional work is MOUSE (murine HSPCs and in vivo AML); the human observation is the recurrent translocation itself. The target-gene list (Hoxa, Meis1, Myb, Myc, Sox4) is given in the abstract in mouse gene nomenclature and is not resolved to specific Hoxa members. The BET-inhibitor efficacy is preclinical.

   ▸Evidence that argues against this (1)

   • A second group's structural work on the same fusion locates it on the CODING REGION of active genes rather than principally at cis-regulatory elements, anchoring NuA4/TIP60 there. The two descriptions imply different mis-targeting geographies and therefore different predictions for what a PWWP-blocking agent would do, and neither can be adjudicated from the abstracts. Cell Rep 2022
5. E5weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.preprint

   In a preprint, neuronal deletion of ZMYND11 in mice causes aberrant upregulation of non-neuronal gene programmes with reduced dendritic branching and spine density and behavioural hyperactivity; ZMYND11 interacts with and inhibits the histone methyltransferase KMT2A (MLL1); a ZMYND11-related-syndromic-intellectual-disability point mutation abrogates that interaction; and in a degron-tagged mouse model the gene-expression changes induced by rapid ZMYND11 degradation in primary cortical neurons are attenuated by treatment with the KMT2A/menin inhibitor revumenib.

   ZMYND11 Restrains KMT2A to Enable a Neuronal Developmental Program · Greben AW, Wu XS, Robb JE, Vogel IR, Traunmüller L, Krüttner S, et al. · bioRxiv 2025
   PMID 41279818DOI
   ▸What this evidence cannot show

   PREPRINT, NOT PEER REVIEWED, and read at abstract level only - the confidence is weak for that reason and not because the design looks poor. NEURONS, not haematopoietic cells, and mouse. The abstract describes revumenib as 'the KMT2A inhibitor', which is loose: revumenib is a menin inhibitor and acts on the menin-KMT2A interface, not on KMT2A catalysis, so the drug arm shows menin-interface dependence rather than methyltransferase dependence. Whether the ZMYND11-KMT2A contact involves the KMT2A N-terminus retained in fusions - the question that would make this relevant to KMT2A::AFF1 - is not answerable from the abstract.

   ▸Evidence that argues against this (1)

   • A preprint reporting a physical interaction between a well-studied reader and the most-studied chromatin enzyme in this field, in 2025, should be read as provisional precisely because the interaction has not previously been reported: ZMYND11[tiab] AND MLL[tiab] returns 0 records and ZMYND11[tiab] AND KMT2A[tiab] returns 4, of which three are neurodevelopmental-genetics papers that do not concern an interaction. Absence of prior report is not refutation, but it sets the prior. NCBI PubMed 2026
6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

   In RS4;11 (KMT2A::AFF1) the hg19 2 kb bin chr10:180,000 reaches 183.0x the MLL1-N track's own genome median - the third-highest of the top thirty bins genome-wide - and under VTP-50469 its MLL1-N within-sample share ratio is 0.133 with MENIN at 0.052.

   Q118 re-analysis of GSE127507, instrument B: 2 kb genome-wide bins from the deposited .deduped.tdf files (RS4;11 MLL1n GSM3635695/96, MENIN GSM3635693/94, input GSM3635699); analyses/q118-menin-at-the-human-index-fusion/results-instrumentB.json, run 2026-09-23 · Iqbal Lab oncofusion knowledge graph 2026
   ▸What this evidence cannot show

   THE MEASUREMENT THAT NAMED THIS GENE IS NOT FUSION-SPECIFIC. The track is MLL1n, Bethyl A300-086A, an MLL1 N-TERMINUS antibody whose epitope is retained in KMT2A::AFF1, so it reads fusion and wild-type MLL1 together at a masking factor the same beat measured as 3.54-4.00x; every statement from it is about MLL1-N-reactive material, never about the fusion. n = 1 per antibody per condition - no replicate exists in GSE127507 - and the depositors measured a Drosophila spike-in and deliberately did not apply it, so cross-condition figures are within-sample shares, not fold changes. SEPARATELY: chr10:180,000 lies within the first 2 kb of chromosome 10's annotated gene content, and bins at chromosome extremities are a recognised source of mapping artefact. The Q118 universe requires input > 0 and excludes blacklisted bins, which is the right control, but the RS4;11 input value AT THIS BIN was not read and this entry does not claim it is clean.

   ▸Evidence that argues against this (1)

   • A very high enrichment at the extreme 5' end of a chromosome arm is exactly where an unasked input question matters most. Until the RS4;11 input track is read at chr10:180,000 - which is minutes of work on files already on disk - 183.0x should be read as a candidate, not a result. Iqbal Lab oncofusion knowledge graph 2026
7. E7strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   On the GRCh37 primary assembly the nearest transcription start to the bin centre chr10:180,000 is ENST00000439456 at 180,405 (405 bp), followed by ENST00000309776, ENST00000381602 and ENST00000397962 at 180,424 and ENST00000509513 at 180,643 - all transcripts of ENSG00000015171 (ZMYND11). The bin is therefore the ZMYND11 promoter and not a neighbouring gene.

   Ensembl GRCh37 REST: lookup/id/ENSG00000015171?expand=1, per-transcript start coordinates · Ensembl · Ensembl GRCh37 archive 2026
   ▸What this evidence cannot show

   Fetched live 2026-09-23. Resolved from a STABLE GENE ID to transcript coordinates - not a name-based lookup, so it cannot make the UCSC longest-match error. These are Ensembl gene models and not experimentally mapped start sites in a leukaemic cell, and a 2 kb bin cannot resolve which of five transcripts within 250 bp is transcribed. The Q118 assignment came from the deposited series' own RefGene windows, a different annotation; the two agree here, which is the point of running the check.

   ▸Evidence that argues against this (1)

   • Agreement between two annotations is weaker evidence than it appears when both descend from the same underlying gene models. The deposited series' ROSE windows are RefGene-derived and this check is Ensembl-derived, and the two share primary sequence and much curation history, so concordance here rules out a gross assignment error and not a shared annotation error. The independent thing this check adds is the DISTANCE (405 bp), which the ROSE window - 6 kb wide - could not have resolved. Iqbal Lab oncofusion knowledge graph 2026
8. E8moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   AML with t(10;17)(p15;q21)/ZMYND11::MBTD1 is a described subtype with minimal differentiation, CD7/CD56 expression and generally poor outcomes in adults, and the fusion has been reported in myeloid/NK-cell precursor leukaemia and as a therapy-related event.

   Acute myeloid leukemia with t(10;17)(p15;q21)/ZMYND11::MBTD1: a subtype with minimal differentiation, CD7/CD56 expression, and generally poor outcomes in adults · Haematologica 2026
   PMID 41262054
   ▸What this evidence cannot show

   Title-level only - the abstract was NOT fetched and read this session, so the cohort size, the outcome metric and the age range behind 'generally poor outcomes in adults' are unknown here, and the claim is written no stronger than the title supports. The companion reports (PMIDs 41454826, 39258225, 31000516, 29911449, 26608508, 23915195) were seen only as titles in an esearch listing and are named as corroborating existence of the entity, not as read sources.

   ▸Evidence that argues against this (1)

   • An entity described across case reports and small series has an outcome literature shaped by reporting bias - unusual and poor-outcome cases are the ones written up. This graph already holds several partner-outcome entries whose lesson is that partner-stratified survival claims frequently fail to replicate, so 'generally poor outcomes' should be held loosely until a registry series exists. Iqbal Lab oncofusion knowledge graph 2026
9. E9moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   Bounded literature counts, 2026-09-23: ZMYND11[tiab] 107; ZMYND11[tiab] AND KMT2A[tiab] 4; ZMYND11[tiab] AND MLL[tiab] 0; ZMYND11[tiab] AND leukemia[tiab] 11; ZMYND11[tiab] AND "H3K36me3"[tiab] 7; ZMYND11[tiab] AND MBTD1[tiab] 9; ZMYND11[tiab] AND "MLL-AF4"[tiab] 0. On the alias: BS69[tiab] 41; BS69[tiab] AND MLL[tiab] 0; BS69[tiab] AND leukemia[tiab] 3.

   PubMed esearch via scripts/pubmed_safe.py, 2026-09-23 · Q119-genes-the-measurement-named · NCBI PubMed 2026
   ▸What this evidence cannot show

   Bounded by TITLES AND ABSTRACTS only (rule 80). One tag per term, no parenthesised group (rule 94); every querytranslation was read back and each expanded to "TERM"[Title/Abstract]. The alias arm BS69 is reported separately and NOT unioned with the ZMYND11 counts. The KMT2A, MBTD1 and H3K36me3 result sets WERE read at title level; the others were not, so those are counts and not reviews. The ZMYND11 AND MLL zero is a real zero in the strict sense - it means no title or abstract pairs those two strings - and it sits beside a 2025 preprint reporting a direct ZMYND11-KMT2A interaction, which is the clearest illustration in this beat of rule 80: a literature bound is a fact about an index, not about the world.

   ▸Evidence that argues against this (1)

   • ZMYND11[tiab] AND MLL[tiab] = 0 would, read carelessly, license the sentence 'ZMYND11 has never been connected to MLL1'. A preprint published five weeks before this query reports exactly that connection and is captured by the KMT2A arm but not by the MLL arm. Both arms were run precisely so that this would be visible. bioRxiv 2025

• binds →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

  PWWP (280-331) reads H3K36me3 ONLY on histone variant H3.3, via the H3.3 Ser31 pocket of the tandem bromo-PWWP module

• inhibits →KMT2A / MLL1 — the gene that breaks

  2025 PREPRINT: ZMYND11 interacts with and inhibits KMT2A/MLL1 in neurons; a ZRSID point mutation abrogates the contact and revumenib attenuates the loss phenotype

• regulates →HOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it

  as the 5' moiety of ZMYND11::MBTD1, directly binds and maintains Hoxa expression in mouse AML - the KMT2A-fusion programme from different parts

• regulates →MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed

  ZMYND11::MBTD1 directly binds and maintains Meis1 expression in mouse AML

• analogous to →KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)

  ZMYND11::MBTD1 is a chromatin-reader 5' module welded to a chromatin-opening 3' module producing HOXA/MEIS1/MYB/MYC - the KMT2A-fusion architecture with different parts

• supports →Instrument check: the top thirty RS4;11 MLL1-N 2 kb bins recovered from a deposited .tdf are JMJD1C (259x the genome median), ZMYND11, BAHCC1, CDK6, MYB, RUNX2, IGF2BP2, FOXP1, SATB1 and ARID1B - canonical KMT2A::AFF1 targets, annotated only against the series' own RefGene windows

  the entry that named this gene; its chr10:180,000 assignment is independently confirmed here as the ZMYND11 promoter (405 bp)

• related to →BRD4 — the best-drugged protein in this beat, and the one whose clinical result is already in and disappointing

  BET inhibition is efficacious downstream of ZMYND11::MBTD1, the drug node of that fusion's acetylation-high state

• related to →KMT2A-rearranged acute myeloid leukaemia in children and infants

  ZMYND11::MBTD1 AML is the minimally differentiated, CD7/CD56-positive comparator entity to KMT2A-rearranged AML

• related to →ARID1B (BAF250b) - the cBAF paralogue whose deletion PROMOTES MLL-AF9 leukaemogenesis, which makes it the one gene in this beat whose published KMT2A-fusion result points the wrong way for a drug target

  both are chromatin proteins in this beat that are simultaneously subunits/readers with their own biology AND recurrent leukaemia fusion partners - a recurring architecture in this disease family

• part of →ZMYND11::MBTD1, t(10;17)(p15;q21) - a chromatin reader welded to the NuA4/TIP60 acetyltransferase, maintaining Hoxa/Meis1/Myb/Myc/Sox4 in AML: the KMT2A-fusion architecture built from different parts

  contributes the 5' half: exons 1-12, carrying the PHD, bromodomain and the H3.3K36me3-reading PWWP - the address module, and the one whose mutation abolishes transformation

• ← fuses withMBTD1 - 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

  t(10;17)(p15;q21); ZMYND11 exons 1-12 to MBTD1 exons 3-17, in frame, 1,054 aa

• ← related toZMYND11::MBTD1 is the KMT2A-fusion architecture assembled from different parts - and the part it throws away is a direct physical brake on KMT2A itself

  the address module; gene-zmynd11 already carries the KMT2A-restraint preprint at abstract level and this entry adds its full text and the MYND localisation

• inhibits →KMT2A / MLL1 — the gene that breaks

  MYND-domain-dependent physical restraint of KMT2A-dependent activation; R600W selectively abolishes the interaction (PREPRINT, mouse neurons and HEK293T)

• 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

  Zmynd11 conditional knockout gains H3K4me3 specifically at highly-ZMYND11-bound transcription start sites, consistent with restraint of KMT2A

• ← depends onZMYND11::MBTD1 AML is menin-inhibitor sensitive despite having no KMT2A rearrangement, because the translocation deletes ZMYND11's MYND domain and with it a physical brake on wild-type KMT2A

  the whole chain runs through ZMYND11's MYND-domain restraint of KMT2A and the fusion boundary at aa 409

• binds →NSD1 - the H3K36 dimethyltransferase whose catalytic activity a NUP98 fusion cannot do without, and which cells can otherwise lose almost for free

  TMT-MS co-IP in mouse brain and HEK293T; R600W selectively strips NSD1 with KMT2A. PREPRINT, no orthogonal validation of the NSD1 arm, no functional NSD1 experiment

• ← related toPHF1 (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

  both read H3K36me3, through a Tudor and a PWWP domain respectively, in two different fusion families. Observation only - no publication connects them and none is claimed