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

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.

• This entry must not be read as a menin-inhibitor rationale. Menin is a TUMOUR SUPPRESSOR in mesenchyme, and the only non-haematologic menin trial with a result, NCT05731947, was terminated by the sponsor after phase 1b for not meeting pre-defined efficacy signals. An MBM-retaining KMT2A fusion in a sarcoma is a test of a hypothesis, not an indication.
• If menin inhibition were tried here off the gene name alone, the predicted direction of effect is not obviously anti-tumour: displacing menin from chromatin in a mesenchymal cell removes a tumour suppressor from its targets. See risk-a-menin-inhibitor-prescribed-off-a-kmt2a-gene-name-in-a-solid-tumour.
• Every quantitative statement about the fusion in this entry is a coordinate derivation from transcript records. If the panel's exon numbering differs from RefSeq's, the frame prediction, the retained-residue count and the MBM claim all move together - one systematic error, not several independent ones.
• DOCK10 is not a dependency in any DepMap arm - both arm means positive, pan-essentiality +0.098 - so there is no inhibitor rationale on the partner side either, and an inhibitor of a CDC42/RAC1 exchange factor would hit a pathway required for normal immune-cell motility.
• The DOT1L link cuts against pinometostat rather than for it: DOT1L is REQUIRED for normal pre-B expansion, marginal-zone B-cell generation and germinal-centre function, and Dock10 is one of the two named marked genes - so the host compartment a DOT1L agent must spare is the one actively depositing the mark.

1. Is the KMT2A::DOCK10 chimera transcribed and in frame? The in-frame call here is a derivation from two RefSeq records; one RT-PCR across the junction on archival S13 material would settle it, and no such experiment has been done on any of the seven cases.
2. Does the retained KMT2A 1-1362 module in this fusion bind menin? Both of this graph's menin hypotheses predict yes, in a lineage where menin is a tumour suppressor and menin inhibitors have never worked - which makes a NEGATIVE result the hypothesis-breaking one.
3. Is the DOCK10 locus H3K79me2-marked in mesenchymal cells, or only in B cells? The published peak is murine and B-lineage, and the answer decides whether the epigenetic link is a lineage coincidence or a property of the gene.
4. Would a chromatin-tethered CDC42/RAC1 exchange factor do anything? The chimera is predicted to carry an intact DOCKER domain behind a CXXC-bearing nuclear address, and nobody has asked whether a GEF has substrates in the nucleus.
5. Is DOCK10 recurrently rearranged in sarcoma at all, or is S13 a singleton? A partner-agnostic RNA-fusion re-analysis of a sarcoma cohort is the instrument and it has not been run.

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

   DOCK10 (Q96BY6) is a 2,186-residue guanine-nucleotide exchange factor for CDC42 and RAC1 carrying a PH domain (181-290), a DOCK-type C2 domain (672-850) and a DOCKER domain (1690-2150), and no chromatin-binding or histone-modifying module of any kind.

   UniProtKB Q96BY6 (DOC10_HUMAN) - Dedicator of cytokinesis protein 10 (Zizimin-3) · UniProt Consortium · UniProtKB 2026
   ▸What this evidence cannot show

   Accession resolved this cycle by gene_exact query with gene_primary read back: exactly one reviewed human record, primary symbol DOCK10, entry DOC10_HUMAN, length 2,186 aa (rules 62 and 65 satisfied; accession AND length asserted so verify-accessions.py can catch a swap). The FUNCTION comment is entirely ECO:0000250 by similarity to MOUSE Dock10 (Q8BZN6) - there is NO experimental human function annotation - and the DOMAIN comment says only that the DOCKER domain 'may mediate some GEF activity', also by similarity. The founding paper reports a 2,180-aa protein against UniProt's 2,186, a six-residue discrepancy not resolved here. Domain boundaries are UniProt feature-table calls, not structures: there is no PDB entry for human DOCK10.

   ▸Evidence that argues against this (1)

   • A domain-architecture argument bounds intrinsic activity, not recruitment. A protein with no recognised chromatin module can still be delivered to chromatin by a partner - this graph's own gene-aff1 is the worked example, scaffolding a route to H3K79 methylation while writing nothing itself. The supportable claim is that DOCK10 has no intrinsic writer, eraser or reader activity, not that it can never be found on chromatin. UniProt Consortium 2026
2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   In human B lymphocytes DOCK10 is an IL-4-inducible gene: IL-4 consistently raises DOCK10 mRNA and protein in CLL and normal peripheral-blood B cells but not in T cells, isoform 3 is enriched in normal B cells and CLL B cells, and the protein distributes between the cytoplasm and the nucleus of CLL cells.

   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
   PMID 18499258DOI
   ▸What this evidence cannot show

   Human primary CLL and normal peripheral-blood B and T cells - the right species and lineage for this graph, but CLL is a mature B-cell neoplasm, not infant KMT2A-rearranged B-ALL, and certainly not a sarcoma. Abstract read from the eutils record; full text not read. The nuclear/cytoplasmic call is immunodetection in CLL cells with no fractionation control stated in the abstract. This is the paper UniProt cites with ECO:0000269 for both of DOCK10's location comments, and unusually for this corpus it genuinely is about that fact - rule 91 checked and PASSED here.

   ▸Evidence that argues against this (1)

   • The later dedicated localisation study finds DOCK-D distribution between cytosol and nucleoplasm is VARIABLE across 11 cell lines and that nuclear predominance is more common for DOCK9 and DOCK11 than DOCK10, and states outright that the cellular localisation of endogenous DOCK proteins is poorly understood. A single-compartment claim for DOCK10 is therefore not supportable and the nuclear pool may be cell-type dependent. Ruiz-Lafuente N et al. 2021
3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   A dedicated study of endogenous DOCK-D proteins found DOCK9, DOCK10 and DOCK11 distributed with variable cytosolic or nuclear predominance across 11 cell lines, found IL-4 raises DOCK10 in mantle-cell lymphoma and diffuse large B-cell lymphoma as well as CLL, and validated a DOCK10 antiserum that marks plasma-membrane ruffles and filopodia in HeLa cells expressing inducible HA-DOCK10.

   Variable Distribution of DOCK-D Proteins between Cytosol and Nucleoplasm in Cell Lines, Effect of Interleukin-4 on DOCK10 in B-Cell Lymphoid Neoplasms, and Validation of a New DOCK10 Antiserum for Immunofluorescence Studies. · Ruiz-Lafuente N, Minguela A, Moraleda JM et al · Antibodies (Basel) 2021
   PMID 34449554DOI
   ▸What this evidence cannot show

   Human cell lines and B-cell lymphoid neoplasms; no sarcoma or mesenchymal line. The study is largely reagent validation in a specialist antibody journal, and its own framing is that endogenous DOCK localisation is poorly understood - it proposes undiscovered nuclear functions rather than demonstrating one. Cytosol/nucleoplasm fractionation is bulk, with no subnuclear resolution. Abstract read; full text not read.

   ▸Evidence that argues against this (1)

   • Rule 74: for an antibody readout the CLONE is the identifier, not the label. This study's stated purpose was to validate a NEW antiserum, which means the earlier CLL localisation result rests on a different, unvalidated reagent - so the two nuclear-pool observations are not the same measurement repeated. Yelo E et al. 2008
4. E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   In case S13 of a pan-sarcoma KMT2A-rearrangement series, an undifferentiated pleomorphic sarcoma carried KMT2A exon 8 fused to DOCK10 exon 2 (NM_014689), one of seven cases in that cohort with KMT2A as the 5-prime partner and a breakpoint downstream of exon 1.

   Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1-KMT2A-YAP1 and VIM-KMT2A fusions. · Massoth LR, Hung YP, Nardi V et al · Modern Pathology 2020
   PMID 32461620DOI
   ▸What this evidence cannot show

   This is ONE patient (case S13, undifferentiated pleomorphic sarcoma) in a commercial targeted RNA-panel series enriched for advanced disease. The source authors call the non-recurrent KMT2A partners of UNCLEAR SIGNIFICANCE and several may be passengers. No fusion protein has been observed for this or any other sarcoma KMT2A fusion by any method, no reciprocal transcript was reported, no functional experiment has been done, and the panel targets specific KMT2A exons, which biases which breakpoints are detectable at all. Supplemental Table 2 reports EXON NUMBERS from the panel's own annotation - the junction nucleotide, the transcript sequence and the reading frame are not given - and it misspells the index gene as KTM2A in two of eighteen rows, so a reader grepping for KMT2A silently loses cases. This graph's parse is at analyses/sarcoma-nonrecurrent-partners/results.json. Naming this case makes it auditable; it does not promote the partner to a driver and it is not a treatment rationale.

   ▸Evidence that argues against this (1)

   • The cohort's recurrent, morphology- and methylation-defined KMT2A sarcoma arms are YAP1-KMT2A-YAP1 and VIM::KMT2A, and those are what the paper's title and conclusions are about. The seven 5-prime non-recurrent cases are explicitly set aside by the authors as of unclear significance, and a targeted panel run in advanced disease will also detect passenger rearrangements. A single MBM-retaining case is a lead, not an entity. Massoth LR et al. 2020
5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   KMT2A exons 1-8 encode aa 1-1362 and therefore retain the menin-binding motif (6-25), LEDGF IBM1 (123-134) and IBM2 (147-152), all three AT-hooks and the CXXC domain (1147-1195); the exon-8 break lies inside the leukaemic breakpoint cluster region (exons 8-14), so the KMT2A portion of this fusion is not distinguishable from that of an infant-leukaemia KMT2A fusion.

   RefSeq NM_001197104.2 / NP_001184033.1 - Homo sapiens lysine methyltransferase 2A (KMT2A), transcript variant 1 · NCBI RefSeq · NCBI Nucleotide 2026
   ▸What this evidence cannot show

   KMT2A exon-to-residue map, re-derived this cycle from RefSeq NM_001197104.2 (CDS 22..11940, 36 exons, NP_001184033.1) and independently reproducing this graph's own ana-kmt2a-exon-to-domain-map: exon 1 = aa 1-144 (MBM 6-25, LEDGF IBM1 123-134), exon 2 = aa 145-168 (IBM2 147-152), exon 3 = aa 168-1052 (all three AT-hooks), exon 4 = 1053-1112, exons 5-6 = 1112-1212 (CXXC 1147-1195). Exon 3 ends at aa 1052, exon 8 at 1362, exon 9 at 1406, exon 15 at 1668, exon 20 at 1888, exon 22 at 1987. All six KMT2A donor exons in this cohort end at a COMPLETE CODON (phase 0), which is why KMT2A can fuse in frame to so many acceptors. Note NM_001197104.2 encodes 3,972 aa while UniProt Q03164 is 3,969 aa; the three-residue difference lies downstream of every coordinate used here. This is a COORDINATE DERIVATION from a transcript record, not a measurement of a fusion protein: no sarcoma KMT2A fusion protein has ever been observed by any method and no menin-binding assay has been run on one.

   ▸Evidence that argues against this (1)

   • Retaining a motif is not the same as presenting it. The chimera's folding, stability and nuclear import are all unmeasured, and a fusion protein can retain a binding motif in primary sequence while failing to engage its partner. This graph's queued test exp-menin-pulldown-on-yky-versus-kmt2a-aff1 exists precisely because retention has never been shown to imply binding for any sarcoma arm. Massoth LR et al. 2020
6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   DOCK10 exon 2 (NM_014689.3, nt 218-337) begins 123 nucleotides after the ATG, an exact multiple of three, so a junction from a phase-0 KMT2A donor exon is predicted to be in frame and the chimera would contribute DOCK10 aa 42-2186 including the PH, DOCK-type C2 and DOCKER domains.

   RefSeq NM_014689.3 - Homo sapiens dedicator of cytokinesis 10 (DOCK10), transcript variant 1, mRNA · NCBI RefSeq · NCBI Nucleotide 2026
   ▸What this evidence cannot show

   A prediction computed this cycle from two RefSeq records, not an observation. Three specific ways it can be wrong: (1) the source reports the commercial panel's own exon numbering, which need not match RefSeq's; (2) the junction nucleotide is unknown, so an intra-exonic breakpoint would change the answer; (3) an in-frame prediction says nothing about whether the transcript is made, escapes nonsense-mediated decay, or is translated. No transcript sequence or protein was reported for this case.

   ▸Evidence that argues against this (1)

   • An in-frame prediction is not a demonstration of a product, and the same calculation returns the opposite answer for other members of this cohort: C2CD3 exon 24 and RALGAPA2 exon 2 both begin at phase 1 and are predicted FRAMESHIFTED, and AHDC1 exon 2 is entirely 5'-untranslated. That the derivation discriminates between cases is a reason to trust the method, not any one result. Massoth LR et al. 2020
7. E7moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   Dock10 is one of exactly two genes named as carrying H3K79me2 peaks at marginal-zone-regulatory loci in developing murine B cells, in the study where DOT1L loss attenuates marginal-zone B cells and bottlenecks the pre-MZ stage - so DOCK10 is a target of the DOT1L/H3K79me2 axis in this graph's own lineage while itself writing, erasing and reading no mark.

   DOT1L-mediated H3K79me2 directs B-cell repertoire establishment, marginal zone development, and germinal center function. · Kealy LC, Russ BE, Turner SJ et al · Journal of Immunology 2026
   PMID 40972012DOI
   ▸What this evidence cannot show

   MURINE conditional knockout in the B lineage - complete genetic loss, not pharmacological DOT1L inhibition - and the link between the H3K79me2 peaks at Lfng/Dock10 and the marginal-zone phenotype is ASSOCIATIVE, with no rescue experiment described in the abstract. This is normal B-lymphopoiesis, not a KMT2A-rearranged system and not a sarcoma. This graph already cites this paper in three entries and already stores Dock10 in mechanism-dot1l-normal-b-lymphopoiesis under data.named_mz_target_genes (rule 82 checked: cited 3 times), so the new content here is the CONNECTION to the sarcoma fusion, not the mark. Bounding queries run 2026-09-22 with one tag per term: DOCK10[tiab] AND histone[tiab] = 1 (this paper), DOCK10[tiab] AND chromatin[tiab] = 1 (PMID 26510930, Parkinson's blood transcriptomics, off topic), against KMT2A[tiab] AND histone[tiab] = 218 through the identical shape. Titles and abstracts only; supporting figures not searched (rule 80).

   ▸Evidence that argues against this (1)

   • An H3K79me2 peak at a gene in normal murine B cells says nothing about whether the DOCK10 locus is marked in a mesenchymal cell, and case S13 is an undifferentiated pleomorphic sarcoma. Worse for the inference: in the fusion the DOCK10 promoter is not what drives transcription - the chimeric transcript comes off the KMT2A promoter - so a regulatory fact about the DOCK10 locus does not transfer to the fusion allele at all. Massoth LR et al. 2020
8. E8moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   DOCK10-mediated CDC42 activation is necessary for amoeboid invasion of melanoma cells, the only well-characterised role for DOCK10 in a non-epithelial tumour; DOCK10 is not a reported gene-fusion partner in any tumour.

   DOCK10-mediated Cdc42 activation is necessary for amoeboid invasion of melanoma cells. · Gadea G, Sanz-Moreno V, Self A et al · Current Biology 2008
   PMID 18835169DOI
   ▸What this evidence cannot show

   Melanoma cells, not sarcoma: DOCK10[tiab] AND sarcoma[tiab] returns 0. The fusion-partner absence was bounded on 2026-09-22 with one tag per term (rule 94): DOCK10[tiab] AND fusion[tiab] = 0, AND translocation[tiab] = 1 (PMID 34449554, the DOCK-D localisation paper, not a rearrangement), AND KMT2A[tiab] = 0, AND MLL[tiab] = 0. Positive controls through the IDENTICAL one-tag-per-term query shape, run 2026-09-22 (rule 67, rule 94): EWSR1[tiab] AND fusion[tiab] = 1,208; EWSR1[tiab] AND translocation[tiab] = 462; AFF1[tiab] AND KMT2A[tiab] = 104; MLLT3[tiab] AND MLL[tiab] = 84; KMT2A[tiab] AND histone[tiab] = 218. Every query was written with one [tiab] per term and its querytranslation read back from the esearch response, so no parenthesised group silently expanded to [All Fields]. Bounded by TITLES AND ABSTRACTS, not by papers (rule 80): supporting figures were not searched. Note also that 'fusion' is a heavily contaminated token in this literature: for CPT1A all 19 hits are mitochondrial or cell fusion and for TMPRSS13 all 9 are viral membrane-fusion protein cleavage, so a raw count on that term must be title-checked before it is read as evidence of anything.

   ▸Evidence that argues against this (1)

   • A PubMed absence cannot see an unreported fusion, and DOCK10 is a 56-exon gene at 2q36 that targeted panels cover unevenly. The supportable reading is that nobody has REPORTED DOCK10 as a fusion partner - a statement about the literature. A partner-agnostic RNA-fusion re-analysis of a sarcoma cohort is the instrument that could change it, and it has not been run. Massoth LR et al. 2020
9. E9weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.dataset

   DOCK10 is not a dependency in either leukaemia arm of this project's own DepMap scan: mean Chronos +0.010 in 11 KMT2A-rearranged lines against +0.091 in 43 other leukaemia lines, difference -0.081, at a pan-essentiality of +0.098 across 1,208 lines.

   DepMap CRISPR (Chronos) gene-effect scan of 11 KMT2A-rearranged versus 43 other leukaemia lines (this project's own scan) · Broad Institute DepMap; joined locally from analyses/depmap-kmt2a-selective-scan-full · analyses/depmap-kmt2a-selective-scan-full 2026
   ▸What this evidence cannot show

   Joined 2026-09-22 from analyses/depmap-kmt2a-selective-scan-full/results.json (generated 2026-09-19T10:12:06Z), this project's own genome-wide scan over 11 KMT2A-rearranged and 43 other leukaemia DepMap lines. NOT re-fetched and NOT independent of that scan: every caveat it carries applies, including that the 11 KMT2A-rearranged lines are drawn from nine individuals and that the arm is myeloid-enriched. The scan records a generation timestamp and NOT a DepMap RELEASE, which is rule 83 exposure carried forward rather than fixed here. Both arm means are POSITIVE, so there is no dynamic range in which selectivity could appear; this row is reported to CLOSE the question rather than to answer it. A rank is not an effect size and a difference is not a dependency (this graph's DepMap rules). Check pan_essentiality_all_lines before reading anything as selective, and note the anti-selective half is 50% of any gene set by construction, with this graph's own base rate at 45.3% - so a tally of genes in that half is the null (rule 84). The decisive limitation here is lineage: the screen is leukaemia lines, and for a sarcoma fusion that is the wrong tissue. Cellosaurus holds 592 KMT2A-commented cell lines and ZERO are sarcoma or any mesenchymal tumour, so no cell-line screen can address these cases at all.

   ▸Evidence that argues against this (1)

   • A knockout screen against the wild-type DOCK10 locus does not test a chimera's requirement for anything, and the predicted product here is a KMT2A-DOCK10 fusion protein. Separately, a selectivity rank near the median is the null and not a result (rule 84), so neither the rank nor the difference carries information. Broad Institute DepMap; joined locally from analyses/depmap-kmt2a-selective-scan-full 2026

• fuses with →KMT2A / MLL1 — the gene that breaks

  KMT2A exon 8 :: DOCK10 exon 2 (case S13); KMT2A 5-prime, aa 1-1362, MBM+CXXC retained, break inside the leukaemic BCR

• part of →Seven KMT2A-rearranged sarcomas retain the menin-binding motif, three of them carry the complete leukaemic N-terminal module, and all sixteen partner names were in one unopened supplementary table

  one of the seven MBM-retaining 5-prime sarcoma partners; one of the three inside the leukaemic BCR

• depends on →Which KMT2A exon carries which interface: exon 1 is the menin-binding motif, exons 5-6 are the CXXC zinc finger (computed, not recalled)

  the retained-module claim is a coordinate derivation against that map, re-verified here from NM_001197104.2

• related to →KMT2A-rearranged soft tissue sarcoma - the same gene as infant B-ALL, in a young adult's leg, as a solid tumour

  partner in case S13, undifferentiated pleomorphic sarcoma

• related to →The predictable clinical error this beat exists to prevent: a menin inhibitor given for a KMT2A-rearranged sarcoma because of the gene name

  an MBM-retaining KMT2A fusion in a sarcoma is exactly the gene-name-driven prescribing risk this entry names

• related to →H3K79me2 builds up as B cells mature - so in B-ALL the drug's target is what the rescued compartment runs on

  Dock10 is one of the two genes named there as H3K79me2-marked marginal-zone regulators - the graph held this without knowing it is also a KMT2A sarcoma partner

• tests →Menin dependency tracks the availability of an intact menin-binding motif, in cis or in trans — not the fusion family

  MBM retained in cis in a mesenchymal tumour: the hypothesis predicts menin sensitivity where menin is a tumour suppressor

• refutes →In leukaemia KMT2A gives the front of the protein; in sarcoma it gives the back. Every consequence follows from that.

  polarity is NOT inverted in this case - KMT2A is 5-prime, which is the leukaemic orientation; the inversion holds for the recurrent arms only

• supports →Every published KMT2A partner in sarcoma, counted - plus the papers this beat read and did not use, so the next beat does not repeat the search without the decisions

  names one of the 16 non-recurrent partners the census recorded as a group because Supplemental Table 2 had not been opened

• related to →Nobody has ever asked whether a KMT2A-rearranged sarcoma needs menin: zero records, and the reason is that no model exists

  an MBM-retaining arm with no menin binding or dependence measurement of any kind - this is one of the cases that absence is about

• tests →The menin interface is a requirement of 5'-KMT2A fusions in haematopoiesis, not of KMT2A rearrangement as such - and a solid tumour has been quietly proving it for six years

  KMT2A 5-prime with a break inside the leukaemic BCR, in mesenchymal tissue: polarity and MBM-in-cis both predict menin sensitivity here, and they cannot be separated by this case

• co-occurs with →TMPRSS13 (MSPL) - a cell-surface serine protease fused in frame to KMT2A exon 20, the clearest NOT-APPLICABLE epigenetics call of the seven, and a symbol whose approved form has a third of its alias's recall

  the two largest predicted in-frame partner contributions, and the two sharpest compartment conflicts: a cytoplasmic GEF and a cell-surface protease behind a nuclear CpG-island reader

• ← co-occurs withCPT1A - 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

  the two extremes of KMT2A retention in the cohort's MPNST and pleomorphic-sarcoma cases: exon 3 (CXXC lost) against exon 8 (inside the leukaemic BCR)