Oncofusion

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Geneestablished confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.Q11b-subtraction

MLLT10 (AF10) — DOT1L cofactor and KMT2A fusion partner

also called AF10 · MLLT10 · ALL1-fused gene from chromosome 10

MLLT10 makes a protein called AF10 that helps an enzyme, DOT1L, put chemical tags on the right genes. When part of MLLT10 is stuck onto the KMT2A gene by a chromosome break, the result is one of the commonest leukemia-causing fusions in children.

The same thing, for a scientist

MLLT10 (ENSG00000078403, chr10:21,524,584-21,743,630, + strand, GRCh38) encodes AF10 (UniProt P55197, 1,068 aa), an obligate cofactor of the H3K79 methyltransferase DOT1L. AF10 is bifunctional: an N-terminal PZP module reads unmodified H3K27 and licenses DOT1L activity, while a C-terminal octapeptide-motif/leucine-zipper (OM-LZ, aa 704-779) binds the DOT1L coiled coil. MLLT10 is a recurrent 3' partner of KMT2A and of PICALM/CALM; in both fusion classes the OM-LZ is retained and the PZP is lost. Whether the loss matters is contested: a DOT1L-dependent addition mechanism fully accounts for transformation by both fusions, and endogenous PZP-containing AF10 is required for transformation by several other fusions. This entry exists as a minimal canonical stub so that subtraction-beat edges resolve; the detailed domain map lives in `protein-mllt10-domains` and the fusion in `fusion-kmt2a-mllt10`.

What it looks like
loading AF-P55197-F1…
AlphaFold AF-P55197-F1 ↗
colourshape

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.

very high (90+)confident (70–90)low (50–70)very low (<50)
I have never read one of these pictures before

A protein is one long chain of amino acids that folds up. The ribbon traces that chain from one end to the other; it is not a wire, it is a simplification of where the backbone runs. Drag to rotate, scroll to zoom.

Domains are the stretches of chain that do a particular job, and they are what the coloured blocks above the picture mark out. Click one and the view flies to it. In this project the important question about any domain is usually whether the fusion still has it — the labels say lost where it does not.

Anything in yellow sticks is a bound small molecule, which is usually the drug.

Go deeper
Why this gene matters to this project

MLLT10 is the KMT2A partner that is said to break the project's retained-half framing. In every other partner examined so far the oncogenic contribution is a module the fusion keeps. Here the claim is that the decisive event is a module the fusion loses: re-supplying the PZP domain in cis to CALM-AF10 abolishes transformation 2. See subtraction-mllt10-pzp for the argument and mech-retained-half-framing-audit for the framing consequences.

Two published results keep this from being settled. First, an addition mechanism already accounts for the disease: MLL-AF10 and CALM-AF10 transformation is abolished by Dot1l knockout and suppressed by the DOT1L inhibitor EPZ004777, so the retained OM-LZ -> DOT1L axis is necessary and sufficient to explain initiation and maintenance without invoking PZP loss [E2 counter, Chen 2013]. Second, endogenous PZP-containing AF10 is REQUIRED for the transforming ability of MLL-AF9, MLL-AF6 and NUP98-NSD1 [E2 counter, Deshpande 2014] - so intact AF10 is not straightforwardly a brake. The honest statement is that PZP loss is a demonstrated contributor in the CALM-AF10 in-cis experiment and an open question everywhere else, including in KMT2A::MLLT10, where the experiment has never been run.

Facts and figures
gene symbolMLLT10
hgnc IDHGNC:16063
ensembl geneENSG00000078403
uniprotP55197
length AA1068
locus10p12.31
alphafold IDAF-P55197-F1
roleDOT1L cofactor; recurrent 3' fusion partner of KMT2A and of PICALM (CALM)
stub noteMinimal canonical entry created by Q11b-subtraction so that subtraction-beat edges resolve. Detailed domain coordinates are in protein-mllt10-domains; fusion biology in fusion-kmt2a-mllt10. Another beat should expand this.
contestedThe 'PZP loss is the decisive event' reading is not settled. Addition suffices: MLL-AF10 and CALM-AF10 transformation is Dot1l-dependent (Chen 2013, PMID 23138183). And intact AF10 is required for transformation by MLL-AF9, MLL-AF6 and NUP98-NSD1 (Deshpande 2014, PMID 25464900).
subnuclear localizationunpublished for wild-type AF10 - no subnuclear observation and no marker co-stain exists in any system
shown for fusionNOT for KMT2A::MLLT10, which has never been imaged. For PICALM::MLLT10 yes: predominantly cytoplasmic across five systems, entirely nuclear under leptomycin B (see localization-calm-af10-predominantly-cytoplasmic).
coordinates grch38
{
  "chromosome": "10",
  "start": 21524584,
  "end": 21743630,
  "strand": 1
}
localization
{
  "subcellular": "CONTESTED. UniProt P55197 says nucleus on one experimental code (ECO:0000269|PubMed:10860745), from a construct-based mapping of a bipartite NLS. The only fractionation of native tissue - mouse testis, PMID 9878787 - finds Af10 as a 140 kDa doublet in BOTH nuclear and cytoplasmic extracts. Endogenous AF10 has never been localised in a haematopoietic cell.",
  "subnuclear": "unpublished. No subnuclear observation of wild-type AF10 exists in any system, and no marker co-stain has ever been performed.",
  "how_shown": "NLS mapping in constructs (PMID 10860745, full text unreadable by all five routes); subcellular fractionation with an in-house polyclonal against the cysteine-rich region (PMID 9878787)",
  "systems": "human construct work of unreadable provenance, and mouse testis; nothing haematopoietic",
  "contradiction": "nucleus (NLS mapping) versus nuclear-and-cytoplasmic (native-tissue fractionation); UniProt carries only the first. Resolving experiment: endogenous AF10 in a blood cell +/- leptomycin B with marker controls.",
  "node": "localization-mllt10-af10-wild-type-nuclear-or-both"
}
cell type
{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "expressed_in": {
    "class": 1,
    "summary": "broadly expressed"
  },
  "required_in": {
    "class": 2,
    "kmt2a_rearranged_lines_mean_gene_effect": -0.096,
    "all_1258_lines_mean_gene_effect": 0.06,
    "pct_all_lines_depleted": 0.6,
    "floor_compressed": false,
    "myeloid_kmt2ar_mean": -0.14,
    "blineage_kmt2ar_mean": -0.02,
    "verdict": "no measurable requirement in any cell type. Same whole-gene-versus-fusion-allele caveat as AFF1 and MLLT1: the DepMap library cuts both alleles, and the panel contains no KMT2A::MLLT10 line at all, so this is not even a test of the fusion context."
  },
  "context": "wild-type protein; there is no KMT2A::MLLT10 or PICALM::MLLT10 line in the matched panel",
  "graph_links": []
}
cell state
{
  "maintains": {
    "class": 3,
    "states": [
      "cell-state-stem-like-self-renewal"
    ],
    "claim": "In murine haematopoietic progenitors, AF10 (MLLT10) FUSION proteins - CALM::MLLT10 in the experiments shown - cause aberrant SELF-RENEWAL of non-stem haematopoietic progenitors, and the MOZ/ENL complex is the recruiting factor that makes it happen. Shown by colony-forming and replating assays.",
    "pmids": [
      "37031220"
    ],
    "rule_80_note": "THIS ENTRY'S ABSENCE CLAIM WAS FALSIFIED BY OPENING THE PAPER. A title-only check of the 29 records scored 37031220 off-topic, because its title ('MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins') names neither a state nor an assay. The full text (PMC10082848, 73,027 characters, opened 2026-09-20) contains 9 occurrences of self-renewal, 3 of colony-forming, and states the self-renewal result in its first sentence. The state literature for MLLT10 is one paper, not zero.",
    "system_named_in_the_claim": "murine haematopoietic progenitors carrying CALM::MLLT10, not KMT2A::MLLT10 and not human infant B-ALL (brief rule 73)"
  },
  "bounded_query": {
    "date": "2026-09-20",
    "tool": "NCBI esearch db=pubmed",
    "query": "(MLLT10[tiab] OR \"AF10\"[tiab] OR \"AF-10\"[tiab]) AND <cell-state clause> AND <leukaemia clause>",
    "count": 29,
    "on_topic_after_title_check": 1,
    "controls": {
      "gene_clause_alone": 587,
      "state_clause_alone": 96743
    },
    "what_the_29_actually_are": "measurable-residual-disease monitoring of KMT2A::MLLT10 and PICALM::MLLT10 transcripts, cytogenetic risk stratification, and fusion-detection method papers. MLLT10 appears in all of them as an RT-PCR or ddPCR target. The one mechanistic record is 37031220 (MOZ/ENL complex recruits leukaemic AF10 fusion proteins), which is a recruitment claim, not a cell-state claim.",
    "reading": "The 29 records are overwhelmingly a diagnostic-assay literature - MLLT10 as an RT-PCR or ddPCR target for residual-disease monitoring. ONE is a real cell-state result (37031220) and the title check missed it; see the rule-80 note above. A naive count of 29 would read as a healthy state literature and a naive title check returns zero; both are wrong.",
    "on_topic_after_opening_full_texts": 1
  },
  "full_texts_opened": [
    "37031220 (PMC10082848) - self-renewal result confirmed present"
  ]
}
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": -0.0962,
  "chronos_mean_other_leukaemia": 0.0525,
  "difference": -0.1487,
  "pan_essentiality_all_lines": 0.0608,
  "selectivity_rank": 491,
  "rank_denominator": 17728,
  "provenance": "Joined 2026-09-21 from analyses/depmap-kmt2a-selective-scan-full (generated 2026-09-19T10:12:06Z), the 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 here, including that the KMT2A-rearranged arm is a small number of lines drawn from nine individuals, that the rank denominator is 17,728 genes, and that a difference is not a dependency. Added because only 26 of 308 gene entries carried this number, which made any KMT2A-selectivity question answerable for 8% of the corpus.",
  "how_to_read": "A negative difference means MORE required in KMT2A-rearranged lines than in other leukaemia lines. A rank near 17,728 is ANTI-selective. Neither is evidence of a fusion-driven dependency on its own: check pan_essentiality_all_lines before calling anything selective, and note that a paralogue-redundant gene can score near zero for reasons that have nothing to do with this disease - see ana-the-paralogue-redundancy-excuse-is-not-tested-and-my-proxy-decided-the-answer."
}
How this could bite us back
  • Any therapy aimed at the AF10-DOT1L interface will also engage wild-type AF10, whose DOT1L cofactor role is required in normal haematopoiesis; on-target toxicity is the expected failure mode.
Still open
  1. What is the normal, non-leukemic function of AF10 in haematopoiesis, and is the untranslocated MLLT10 allele haploinsufficient in KMT2A::MLLT10 patients?
  2. MLLT10 partners with both KMT2A and PICALM. Do the two fusion classes converge on the same transcriptional output, and does the shared PZP loss explain the convergence?
  3. If endogenous AF10 is required for MLL-AF9, MLL-AF6 and NUP98-NSD1 transformation (Deshpande 2014) while AF10's own PZP module is said to be a constraint that AF10 fusions escape (Klein 2021), what does AF10 actually do in a KMT2A::MLLT10 cell - is the endogenous allele still supplying the required cofactor function while the fusion supplies the unconstrained one? Nobody has looked.
Every source behind this entry (2)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    MLLT10 is human gene ENSG00000078403 on chromosome 10 (21,524,584-21,743,630, plus strand, GRCh38), described by HGNC as 'MLLT10 histone lysine methyltransferase DOT1L cofactor'; it encodes UniProt P55197 (AF10_HUMAN), 1,068 aa.

    Ensembl gene ENSG00000078403 (MLLT10) and UniProtKB entry P55197 (AF10_HUMAN) · Ensembl / UniProt Consortium · Ensembl REST and UniProt REST 2026
    What this evidence cannot show

    Coordinates are GRCh38 and will differ in GRCh37. Both records fetched and checked on 2026-09-18; the UniProt entry is the human protein, not the mouse orthologue.

    Evidence that argues against this (1)
    • A canonical gene record is the wrong coordinate system for a fusion beat, and this entry's residue numbers inherit that problem. Meyer et al. sequenced genomic breakpoints in 2,345 acute leukaemia patients, identified 135 distinct MLL rearrangements with 94 partner genes characterised at the molecular level, and found the MLL-side breakpoint itself shifts with age and lineage (intron 11 in ALL and younger patients, intron 9 in AML and older patients), which they read as different aetiologies in different age groups. What a KMT2A::MLLT10 fusion actually contains of AF10 is set by the patient's breakpoint, not by the canonical transcript of ENSG00000078403, so 'PZP (22-198) lost, OM-LZ (704-779) retained' is a statement about the reference protein that has never been checked against a breakpoint distribution for MLLT10 specifically. Meyer C et al. 2018
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    The PZP domain of AF10 is consistently impaired or deleted in leukemogenic AF10 translocations, and incorporating a functional PZP into CALM-AF10 in cis prevents transformation of bone-marrow HSPCs and abrogates leukemogenesis in vivo.

    The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations · Klein BJ, Deshpande A, Cox KL, Xuan F, Zandian M, Barbosa K, Khanal S, Tong Q, Zhang Y, Zhang P, Sinha A, Bohlander SK, Shi X, Wen H, Poirier MG, Deshpande AJ, Kutateladze TG · Nature Communications 2021
    PMID 34226546DOI
    What this evidence cannot show

    Demonstrated for CALM-AF10, not KMT2A::MLLT10. Mouse models. Verified against PubMed on 2026-09-18.

    Evidence that argues against this (2)
    • A sufficient ADDITION mechanism for AF10 fusions already exists, and it does not require PZP loss to explain anything. Chen et al. showed that MLL-AF10 AND CALM-AF10 transformation is dependent on the H3K79 methyltransferase Dot1l by both genetic and pharmacological means: conditional Dot1l knockout abolished in vitro transformation of murine bone marrow cells and in vivo initiation and maintenance of MLL-AF10 and CALM-AF10 leukaemia, and the selective inhibitor EPZ004777 suppressed Hoxa-cluster and Meis1 expression and impaired proliferation of transformed cells. The retained OM-LZ recruits DOT1L; DOT1L activity is necessary and its loss is sufficient to abolish the disease. Nothing in that chain needs the discarded PZP. The subtraction interpretation is an additional claim layered on a mechanism that is already complete. Chen L et al. 2013
    • Intact, PZP-containing AF10 is a POSITIVE requirement for leukaemogenesis in other fusion contexts, which is awkward for a framing in which losing PZP is the oncogenic event. Deshpande et al. showed that AF10 inactivation reverses leukaemia-associated epigenetic profiles, precludes abnormal HOXA gene expression, and impairs the transforming ability of MLL-AF9, MLL-AF6 and NUP98-NSD1 - three mechanistically distinct HOX-activating oncogenes. So wild-type AF10 is not a brake that the fusion escapes; in those settings it is an accessory the oncogene needs. Whether AF10 is a constraint or a requirement evidently depends on whether it is the fusion partner or the endogenous cofactor, and the entry should not present the PZP-loss reading as the settled account of what MLLT10 contributes. Deshpande AJ et al. 2014
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