Oncofusion

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Genemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q45-immunophenotype

KIT / CD117 - the most myeloid-specific antigen in the lineage-assignment panel, and the mutation that is mutually exclusive with KMT2A rearrangement

also called KIT · CD117 · c-kit · SCFR · Mast/stem cell growth factor receptor Kit · proto-oncogene c-Kit · P10721

CD117 is a receptor for stem cell factor and is the single best flow marker for deciding that a blast is myeloid rather than lymphoid - much better than the CD13 and CD33 that panels traditionally relied on. In KMT2A-rearranged leukaemia it matters twice: it helps call a lineage switch, and mutations in the same gene almost never occur alongside a KMT2A rearrangement.

The same thing, for a scientist

KIT (UniProt **P10721**, KIT_HUMAN, **976 aa**, single reviewed human record, synonym SCFR) encodes the stem cell factor receptor tyrosine kinase, known in flow cytometry as **CD117**. This graph names it in 13 entries with no entry of its own. **Its diagnostic value is quantified and is better than the markers it is usually listed beside.** In 104 consecutive acute leukaemias immunophenotyped with the same fluorochrome, **calculated specificity for myeloid involvement was 0.86 for CD117 against 0.36 for CD13 and 0.44 for CD33 (P < 0.005)**. CD117 was detected in 91% of AML and MDS, and every negative case was acute monocytic leukaemia. CD117 was positive in four ALL cases, **none of which had bcr/abl or MLL rearrangements**. The authors argued CD117 should score at least one point in the biphenotypic-leukaemia scoring system on those grounds [E1]. **Two things follow directly for this beat.** 1. **CD117 is the marker to use for calling a myeloid shift**, and a panel that relies on CD13 and CD33 - which is what the classical KMT2A-rearranged "aberrant myeloid antigen" description rests on - is using the two weakest members of the set. Specificity 0.36 and 0.44 are barely better than chance for lineage assignment. 2. **Every negative AML case was monocytic**, and KMT2A-rearranged AML is characteristically FAB M5 / monocytic - in 967 paediatric AML, KMT2A-r was associated with FAB M5 [E2]. **So the best myeloid marker is systematically weakest in exactly the myeloid phenotype this disease produces.** A lineage-switch panel built on CD117 will under-call switches into monoblastic AML, which is the commonest destination. **And the gene is a genetic as well as an immunophenotypic fact.** In the same 967-patient paediatric AML cohort, KMT2A rearrangements were **mutually exclusive with KIT mutations (P = .036)**, alongside mutual exclusivity with NPM1, WT1 and CEBPA mutations and with NUP98::NSD1, RUNX1::RUNX1T1 and CBFB::MYH11 [E2]. KIT mutation is a core-binding-factor AML lesion; KMT2A rearrangement is not.

Go deeper
The monocytic blind spot, stated plainly

This is the sharpest usable finding in this entry, and it is an inference from two independent results that neither paper draws.

  • CD117 has specificity 0.86 for myeloid involvement, and the only CD117-negative AML cases in that series were acute monocytic leukaemias 1.
  • KMT2A rearrangement in paediatric AML is associated with FAB M5 (monocytic) 2, and the commonest lineage switch in KMT2A-rearranged B-ALL is to AML, frequently monoblastic - this graph's own pt-story-infant-all-kmt2a-aff4-blinatumomab-lineage-switch records a switch to CD19-negative monoblastic AML.

Therefore the best available myeloid confirmation marker is the one most likely to be negative in the specific myeloid disease these patients switch into. This is the same family of failure as the B-lineage MRD panel scoring a switched blast as remission (concept-mrd-flow-cytometry-and-the-lineage-switch-blind-spot), one level deeper: even a panel that includes myeloid markers can miss a monocytic switch if CD117 is the myeloid anchor.

The mitigation is monocytic markers, not more stem markers: CD14, CD64, CD11b, CD4-dim, lysozyme. Current lineage-assignment frameworks define myeloid lineage by MPO or monocytic differentiation precisely for this reason 3.

Cell type, cell state, localisation, epigenetics
  • Cell type. Haematopoietic stem and progenitor cells, mast cells, and non-haematopoietic: melanocytes, germ cells, interstitial cells of Cajal. CD117-directed therapy is therefore not haematopoiesis-restricted.
  • Cell state. A progenitor/stem-associated receptor; its co-expression with cytoplasmic CD79a is often accompanied by CD7 reactivity, which the authors read as suggesting a stem cell disorder 1 - the same CD117/CD79a/CD7 triple that appears in KMT2A-rearranged ambiguous-lineage cases.
  • Localisation. Plasma membrane, type I transmembrane receptor tyrosine kinase, 976 residues, with an extracellular five-Ig-domain ligand-binding region and a split intracellular kinase domain 4.
  • Epigenetics. Nothing in this beat places the KMT2A fusion at the KIT locus. KIT is relevant here as a lineage-assignment reagent and as a mutually exclusive genetic lesion, not as a fusion target gene.
Facts and figures
uniprotP10721
gene symbolKIT
length AA976
cd numberCD117
monocytic blind spotall CD117-negative AML cases in that series were acute monocytic; KMT2A-r AML is associated with FAB M5 (PMID 34638301); the commonest lineage switch destination is AML, frequently monoblastic
mutual exclusivityKMT2A-r mutually exclusive with KIT MUTATION (P=.036) in 967 paediatric AML; a genetic fact, not an expression fact (PMID 34638301)
accession resolutiongene_exact:KIT AND organism_id:9606 AND reviewed:true, fields include gene_primary and length; one row; primary name read back as KIT; length 976 asserted for verify-accessions.py.
myeloid specificity
{
  "CD117": 0.86,
  "CD13": 0.36,
  "CD33": 0.44,
  "p": "<0.005",
  "n": 104,
  "threshold_pct": 10,
  "pmid": "10229319",
  "title": "Enhanced myeloid specificity of CD117 compared with CD13 and CD33.",
  "authors": "Nomdedéu JF, Mateu R, Altès A, et al.",
  "venue": "Leuk Res",
  "year": 1999,
  "title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
}
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": -0.029,
  "chronos_mean_other_leukaemia": -0.0623,
  "difference": 0.0333,
  "pan_essentiality_all_lines": -0.0544,
  "selectivity_rank": 13216,
  "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
  • A lineage-switch panel anchored on CD117 will under-call the commonest switch. Every CD117-negative AML case in the specificity study was acute monocytic, and KMT2A-rearranged AML is characteristically FAB M5 and monoblastic. The best myeloid marker is systematically weakest in the exact myeloid disease these patients switch into; monocytic markers (CD14, CD64, CD11b, lysozyme) must be in the panel.
  • CD13 and CD33 have myeloid specificity of 0.36 and 0.44 against a consensus lineage definition. The classical 'KMT2A-rearranged B-ALL co-expresses myeloid antigens' description rests substantially on those two, so a large part of that description is built on markers that barely discriminate lineage.
  • CD117 is on non-haematopoietic tissue - melanocytes, germ cells, interstitial cells of Cajal - so a CD117-directed therapeutic inherits the toxicity profile of KIT inhibition rather than of a leukaemia antigen, and the patients are infants in whom those tissues are developing.
  • KIT mutation and CD117 expression are constantly conflated. The mutual exclusivity of KIT mutation with KMT2A rearrangement says nothing about CD117 surface expression, and any argument that moves between the two without saying so is wrong.
Still open
  1. What fraction of KMT2A-rearranged AML, and of post-switch monoblastic AML, is CD117-negative? The two results this entry connects come from different cohorts and nobody has measured the intersection.
  2. Does adding monocytic markers to an MRD panel recover the switches a CD117-anchored panel misses? This is a re-analysis of existing paired diagnostic and relapse flow files, not a new experiment.
  3. Is the CD117/cytoplasmic-CD79a/CD7 triple enriched in KMT2A-rearranged ambiguous-lineage cases specifically? It was noted in passing in 1999 and appears not to have been followed up in this genotype.
  4. Does CD117 change under menin inhibition? The revumenib immunophenotype study reports switches between myeloid/stem-like and monocytic phenotypes, which is exactly the axis on which CD117 would move.
Every source behind this entry (4)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In 104 consecutive acute leukaemia cases (55 AML, 23 B-lineage ALL, 3 T-ALL, 11 blast crises of chronic myeloproliferative disorders, 12 MDS with more than 10% blasts) analysed with CD13, CD33 and CD117 conjugated to the same fluorochrome and a 10% positivity threshold, calculated specificity for myeloid involvement was 0.86 for CD117, 0.36 for CD13 and 0.44 for CD33 (P < 0.005). CD117 expression was detected in 91% of AML and MDS, and all the negative cases corresponded to acute monocytic leukaemias. CD117 was also positive in four cases of ALL, none of which showed bcr/abl or MLL rearrangements. The coexpression of CD117 with cytoplasmic CD79a is often associated with CD7 reactivity, suggesting a stem cell disorder, and the authors argue CD117 should score at least one point in the biphenotypic acute leukaemia scoring system.

    Enhanced myeloid specificity of CD117 compared with CD13 and CD33. · Nomdedeu JF, ..., Rubiol E · Leuk Res 1999
    PMID 10229319DOI
    What this evidence cannot show

    Abstract read in full from raw efetch XML on 2026-09-20; full text not read. **n = 104 from one hospital in 1999, with only 3 T-ALL cases**, and lineage was assigned by EGIL criteria, which have since been superseded - so 'specificity for myeloid involvement' is specificity against a 1995 consensus definition rather than against a molecular truth. The 10% positivity threshold is this laboratory's choice. **The number of MLL-rearranged cases in the series is not stated in the abstract**, so this paper does not establish CD117's behaviour in KMT2A-rearranged disease specifically; the monocytic finding is a general AML finding that this entry then connects to the KMT2A-r monocytic association from a different cohort [E2].

    Evidence that argues against this (1)
    • A 1999 three-marker comparison cannot settle lineage assignment in 2026. Current WHO and ICC frameworks define myeloid lineage by MPO or evidence of monocytic differentiation and assign CD117 a supporting rather than defining role, so the argument to increase CD117's score in a biphenotypic scoring system has been overtaken rather than adopted. Leventaki V et al. 2026
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Among 967 paediatric AML patients with known KMT2A-r status characterised by morphology, multicolour flow cytometry, cytogenetics and panel sequencing, 241 (24.9%) showed KMT2A rearrangement. KMT2A-r was associated with FAB M5, a high white blood cell count and younger age at diagnosis. KMT2A rearrangements were mutually exclusive with mutations in NPM1 (P = .002), KIT (P = .036), WT1 (P < .001) and CEBPA (P = .006) and with the translocations NUP98/NSD1 (P = .009), RUNX1/RUNX1T1 (P = .003) and CBFB/MYH11 (P = .006), and FLT3-ITDs were detected less frequently in AML with KMT2A-r (P < .001). A positive correlation existed with KRAS mutations (P < .001) with no prognostic impact.

    Impact of KMT2A Rearrangement and CSPG4 Expression in Pediatric Acute Myeloid Leukemia. · Hoffmeister LM, ..., Schneider M · Cancers (Basel) 2021
    PMID 34638301DOI
    What this evidence cannot show

    Abstract read in full from raw efetch XML on 2026-09-20; full text not read. **Mutual exclusivity at P = .036 among many simultaneous comparisons in one abstract is a weak signal with no stated multiplicity correction**, and KIT mutations are uncommon outside core-binding-factor AML, so the exclusivity may largely reflect the separate exclusivity with RUNX1::RUNX1T1 and CBFB::MYH11 rather than an independent KMT2A-KIT relationship. Panel sequencing detects only the KIT regions on the panel. **This is KIT mutation, an entirely different quantity from CD117 surface expression**, and the two are conflated constantly in this literature.

    Evidence that argues against this (1)
    • KIT mutation and CD117 protein expression are different measurements and this entry must not let one stand for the other: CD117 is expressed in 91% of AML regardless of KIT mutational status, so 'KMT2A-r is mutually exclusive with KIT mutation' implies nothing at all about whether KMT2A-r blasts are CD117-positive. Nomdedeu JF et al. 1999
  3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.review

    Mixed phenotype acute leukaemia is characterised by discrete admixed populations of myeloid and lymphoid blasts, or by co-expression of lymphoid and myeloid markers in a single blast population, and accurate classification relies heavily on multiparameter flow cytometry integrated with cytogenetic and molecular studies. The current World Health Organization classification and International Consensus Classification recognise specific genetic subtypes including MPAL with t(9;22)/BCR::ABL1 and MPAL with KMT2A rearrangement, and distinct genetic lesions appear to correlate with specific immunophenotypic patterns.

    PMID 42349662DOI
    What this evidence cannot show

    **A narrative review, cited as a map of current classification rather than as a measurement.** Abstract read in full from raw efetch XML on 2026-09-20; full text not read. The abstract does not enumerate the specific marker thresholds for lineage assignment, so this entry's statement that myeloid lineage is defined by MPO or monocytic differentiation is the widely used WHO/ICC rule and is **not** directly quoted from this abstract - a reader needing the exact criteria should consult the classification documents.

    Evidence that argues against this (1)
    • That MPAL with KMT2A rearrangement is now a named genetic entity means the immunophenotype is no longer what defines these patients - the genotype is. That undercuts the whole project of using a marker panel to assign lineage in this disease, and it is the strongest argument in this beat for lineage-independent molecular monitoring instead. Kovach AE et al. 2026
  4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    KIT is UniProt P10721 (KIT_HUMAN), Mast/stem cell growth factor receptor Kit (SCFR, EC 2.7.10.1, Piebald trait protein, proto-oncogene c-Kit, tyrosine-protein kinase Kit, CD antigen CD117), 976 amino acids, a single reviewed human record with primary gene name KIT and gene synonym SCFR.

    What this evidence cannot show

    Fetched 2026-09-20 with `gene_exact:KIT AND organism_id:9606 AND reviewed:true`, requesting `gene_primary` and `length` per rules 62 and 65; primary name read back as KIT; exactly one reviewed row; length 976 asserted for `verify-accessions.py`. **The symbol KIT is an ordinary English word and a common abbreviation**, so any literature count keyed on it without a disease term is unusable - the same class of trap as `SEPT*` matching September. The searches behind this entry were run as `(CD117 OR KIT) AND (KMT2A OR MLL) AND leukemia` and title-checked.

    Evidence that argues against this (1)
    • The 1999 paper that supplies this entry's specificity numbers describes CD117 as a 145 kDa receptor, which corresponds to the mature glycosylated protein rather than the 976-residue translated sequence. Neither number tells a reader what a CD117 flow antibody detects or at what threshold, and the 10% positivity cut-off is a laboratory convention. Nomdedeu JF et al. 1999
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