KMT2A::MAML2 type B2/B3 thymoma - the same fusion, a different organ, a different disease
also called KMT2A-MAML2 thymoma · fusion-positive type B thymoma · thymic epithelial tumour with KMT2A-MAML2
The same KMT2A fusion that causes leukaemia in children also causes a tumour of the thymus in middle-aged adults. That one fusion produces two completely different diseases depending on which cell it lands in is the clearest natural experiment this graph has about what a fusion needs in order to cause leukaemia.
The same thing, for a scientist
KMT2A-MAML2 is the first recurrent gene fusion described in type B thymoma: 11 fusion-positive patients in a 255,008-sample comprehensive-genomic-profiling cohort, 4% of all thymomas (10/242) and 6% of B2/B3 histology (10/169), median age 48 (range 29-69), 55% male, with concurrent genomic alterations infrequent and one case showing foci of thymic carcinoma [E1]. The junctions are KMT2A exon 8, 9, 10 or 11 to MAML2 exon 2 - the same fusion architecture as the leukaemia cases, on the same side of the major BCR [E1][E2]. A paralogous KMT2A::MAML3 fusion has since been described in a type B3 thymoma [E3]. **The scientific value of this entry is comparative.** The identical fusion produces an indolent-to-locally-invasive epithelial neoplasm in a middle-aged adult thymus and an acute leukaemia in a child's marrow. Fusion identity is therefore not sufficient to specify disease; cell of origin is doing at least as much work. And because the fusion retains the menin-binding motifs in both tissues, the question of whether KMT2A::MAML2 thymoma is menin-dependent is a clean, answerable test of whether the menin interface is a property of the fusion or a property of the haematopoietic context. **Nobody has asked it: (MLL OR KMT2A) AND MAML2 AND menin returns zero PubMed records** [E4].
Why a thymoma entry belongs in a leukaemia knowledge graph1 deeper
Because it is a controlled comparison the field cannot otherwise run. The oncogene is held constant - the same 5' partner, the same 3' partner, the same acceptor exon, junctions within the same breakpoint region - and the cell is varied. What changes:
| KMT2A::MAML2 leukaemia | KMT2A::MAML2 thymoma | |
|---|---|---|
| cell of origin | haematopoietic progenitor | thymic epithelial cell |
| age | children and adults; several paediatric | median 48, range 29-69 |
| antecedent | usually cytotoxic therapy for a prior cancer | none reported |
| tempo | acute leukaemia | epithelial neoplasm, B2/B3 histology |
| co-lesions | not systematically assessed | infrequent |
| n | ~8 reported cases | 11 patients, 4% of thymomas |
The last row is worth pausing on: the fusion is more common in thymoma than in leukaemia. The thymoma disease is the fusion's main setting, and the leukaemia is the rarity - which is the reverse of how a KMT2A-centric reading would frame it.
The 'infrequent concurrent alterations' observation
Massoth et al. report that concurrent genomic alterations were infrequent in the fusion-positive thymomas 1. Thymomas in general have a low mutational burden, and the paper opens by noting the lack of prognostic or targetable genetic alterations in the disease 1. So in this tissue the fusion looks close to a solitary driver.
That sits interestingly against the leukaemia side, where a KMT2A fusion in a child's marrow is famously close to a solitary driver too - the low-mutation-burden character of infant KMT2A-rearranged ALL is one of this project's recurring themes. Two tissues, one fusion, few co-operating lesions in either, and two entirely different diseases. If co-operating mutations are not what distinguishes them, the difference is chromatin state and cell identity, which is precisely the axis this graph cares about.
What this does to the menin-interface hypothesis1 deeper
The fusion retains MBM1 and MBM2 by position in both tissues - the KMT2A donor exons are 8-11, comfortably 5' of everything the major BCR removes. So on the graph's standing model, KMT2A::MAML2 thymoma should be menin-dependent.
If it is, that is a striking extension: the menin interface would be a property of the fusion protein itself rather than of the haematopoietic context, and an approved drug class would have a rationale in a solid tumour with no targeted options at all. If it is not, then menin dependence requires something the thymic epithelial cell does not supply, and the menin interface is contextual rather than intrinsic - which would be a real constraint on how far the hypothesis generalises, and would raise the question of what that missing context is in leukaemia.
Either answer is informative, the experiment is a straightforward one on primary or PDX thymoma material, and it has not been done. It is written up as exp-menin-dependence-kmt2a-maml2-thymoma.
What would make this not a clean test
Two things, stated so the experiment is not oversold.
- No KMT2A::MAML2 thymoma model exists. No cell line, no PDX in the public domain. The test needs primary tissue or a model built first, and thymomas are resected rather than biopsied repeatedly, so material is scarce.
- A negative result is ambiguous. Menin has tissue-specific functions of its own - this graph holds several entries on menin in normal endocrine tissue - so failure of a menin inhibitor in thymoma could reflect thymic epithelial menin biology rather than absence of a fusion-menin interaction. Co-immunoprecipitation of menin with the fusion from thymoma tissue is the more direct and less ambiguous first step.
A third tissue, and a caution about it
KMT2A rearrangement also characterises a subset of paediatric parotid mucoepidermoid carcinomas arising metachronous to acute lymphoblastic leukaemia; KMT2A-rearranged cases in that series had significantly worse overall survival than KMT2A-intact metachronous cases (p = 0.027), and no KMT2A rearrangement was found in primary paediatric mucoepidermoid carcinomas 5.
The caution: that paper's abstract, as indexed, does not state that MAML2 is the partner in the KMT2A-rearranged cases, and mucoepidermoid carcinoma's classical fusion is CRTC1::MAML2, a different 5' partner entirely. This entry therefore records the third-tissue observation as KMT2A-rearranged metachronous mucoepidermoid carcinoma and explicitly does not claim those tumours carry KMT2A::MAML2. Conflating the two would be exactly the kind of family-resemblance error this beat was warned about.
| tissue | thymus, thymic epithelial cell |
|---|---|
| histology | WHO type B2 and B3 thymoma; one case with foci of thymic carcinoma |
| n fusion positive | 11 |
| frequency all thymoma PCT | 4 |
| frequency b2 b3 PCT | 6 |
| median age years | 48 |
| sex | 55% male |
| concurrent alterations | infrequent |
| junctions | KMT2A exon 8, 9, 10 or 11 to MAML2 exon 2 - within the major BCR, i.e. the PHD fingers are lost, as in the leukaemia form |
| paralogue case | one type B3 thymoma with KMT2A::MAML3 |
| menin dependence | NEVER TESTED. Zero PubMed records for the KMT2A/MAML2/menin intersection. The fusion retains MBM1 and MBM2 by position, so the graph's standing model predicts dependence. |
| models available | none - no KMT2A::MAML2 thymoma cell line or public PDX exists |
| comparative value | the same fusion, same architecture, in a non-haematopoietic cell, producing a different disease at a different age with no antecedent therapy. Holds the oncogene constant and varies the cell. |
| third tissue caution | KMT2A-rearranged paediatric metachronous parotid mucoepidermoid carcinoma is a related observation but the partner is NOT stated to be MAML2 and this entry does not claim it is. |
denominators — the numbers behind the chart
{
"all_thymomas_profiled": 242,
"b2_b3_thymomas": 169,
"total_cancers_profiled": 255008
}age range years
[ 29, 69 ]
- If menin inhibitors work in KMT2A::MAML2 thymoma, the eligible population is middle-aged adults with a chronic epithelial tumour, treated for years rather than months. The menin-inhibitor class carries a documented endocrine and multi-organ hyperplasia signal on prolonged exposure, and this graph already holds entries on exposure duration versus MEN1 latency. Long-duration dosing in a non-fatal tumour is a different risk calculation from short-course therapy in acute leukaemia.
- A negative menin result in thymoma would not cleanly falsify the menin-interface hypothesis, because menin has thymic and epithelial functions of its own that could confound a growth readout. Co-immunoprecipitation of menin with the fusion from tumour tissue is the less ambiguous first experiment.
- The fusion is commoner in thymoma than in leukaemia. A leukaemia-centred research programme is therefore studying the minority setting of its own oncoprotein, and any mechanistic account built only on the leukaemia cases is at risk of being the special case rather than the general one.
- Is KMT2A::MAML2 thymoma menin-dependent? The single highest-value unanswered question in this beat, because either answer constrains the menin-interface hypothesis and one of them opens an approved drug class to a tumour with no targeted options.
- Why a thymic epithelial cell? Thymic epithelium is not a KMT2A-fusion tissue in any other context. Does it share a chromatin feature with the haematopoietic progenitor - an open HOXA cluster, a particular CpG landscape - or is the shared feature simply that both are places where this inversion can occur and be tolerated?
- Does the fusion induce HOXA genes in thymoma? If the canonical KMT2A-r programme runs in an epithelial cell, that is strong evidence the programme is intrinsic to the fusion. If it does not, cell context dominates. Nobody has looked, in either tissue, for this fusion.
- Are the thymoma patients' tumours clonally related to any haematological abnormality? Thymomas are associated with autoimmune and haematological phenomena, and no one has asked whether the fusion is detectable in the blood of these patients.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Eleven patients had thymomas harbouring a KMT2A-MAML2 fusion with breakpoints between KMT2A exon 8, 9, 10 or 11 and MAML2 exon 2; 55% were men with a median age of 48 at surgery (range 29-69); concurrent genomic alterations were infrequent; all were B2 or B3 histology with one showing foci of thymic carcinoma; and the fusion was present in 4% of all thymomas (10/242) and 6% of B2/B3 thymomas (10/169), making it the first recurrent fusion described in type B thymoma.
Pan-Cancer Landscape Analysis Reveals Recurrent KMT2A-MAML2 Gene Fusion in Aggressive Histologic Subtypes of Thymoma. · Massoth LR, Hung YP, Dias-Santagata D, Onozato M, Shah N, Severson E, Duncan D, Gillespie BJ, Williams NF, Ross JS, Vergilio JA, Harkins SK, Glomski K, Nardi V, Zukerberg LR, Hasserjian RP, Louissaint A, Williams EA · JCO Precision Oncology 2020What this evidence cannot show
A commercial comprehensive-genomic-profiling cohort of advanced cancers, so the 242 thymomas are enriched for advanced, recurrent or refractory disease and the 4% figure may not transfer to resected early-stage thymoma seen in general practice. Only a portion of samples had RNA profiling, so fusion ascertainment was not uniform. Eleven fusion-positive patients in total but 10 inside the 242-thymoma denominator, which is why the two counts differ. No functional work, no treatment data, no survival comparison against fusion-negative B2/B3 thymoma. Abstract read in full.
Evidence that argues against this (1)
- A KMT2A::MAML3 fusion has since been found in a type B3 thymoma sharing the same downstream domains, so the recurrent thymoma lesion is a KMT2A-MAML-family fusion and a MAML2-keyed frequency is a floor. Reviews of thymic-tumour fusion biology also place other fusion events in thymic epithelial tumours, so KMT2A-MAML2 is not the only one. Zhou Z et al. 2025
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The leukaemia form of the same fusion joins MLL exon 7 to MAML2 exon 2 and produces a protein losing MAML2's Notch-binding basic domain, so the thymoma and leukaemia fusions share architecture and differ only in the exact KMT2A donor exon.
Identification of a novel fusion gene MLL-MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23). · Nemoto N, Suzukawa K, Shimizu S, Shinagawa A, Takei N, Taki T, Hayashi Y, Kojima H, Kawakami Y, Nagasawa T · Genes, Chromosomes & Cancer 2007What this evidence cannot show
Two leukaemia patients. Exon numbering conventions are not stated to be identical between this paper and the thymoma series, so 'exon 7' here and 'exon 8-11' there may not be on exactly the same scale - though both fall within the major BCR on any plausible convention. Abstract read in full.
Evidence that argues against this (1)
- Identical fusion architecture at the exon level does not guarantee an identical protein: alternative splicing, isoform usage and post-translational context differ between a thymic epithelial cell and a haematopoietic progenitor, and no one has compared the fusion protein from the two tissues. Massoth LR et al. 2020
- E3weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper
A novel KMT2A::MAML3 fusion has been reported in an invasive type B3 thymoma, detected by RNA sequencing after DNA-based NGS found no pathogenic variants, with MAML3 and MAML2 described as paralogues sharing similar functional domains at their exon 2 fusion sites.
Type B3 Thymoma With a Novel KMT2A::MAML3 Fusion: Expanding the Spectrum of Gene Fusions Beyond the MAML2 Gene. · Zhou Z, Yu Y, Chen C, Lin J · Genes, Chromosomes & Cancer 2025What this evidence cannot show
One patient. The proposed Notch mechanism is explicitly a hypothesis and untested. Reported intratumour heterogeneity (trabecular and fascicular patterns, clear-cell areas) means the fusion's relationship to any one morphology in that tumour is uncertain. Abstract read in full.
Evidence that argues against this (1)
- One case cannot establish MAML3 fusions as recurrent in thymoma, and treating MAML3 as interchangeable with MAML2 on the strength of a sequence alignment extends an 11-patient finding by a single sample. Massoth LR et al. 2020
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
No published work connects KMT2A-MAML2 to menin in any tissue: (MLL OR KMT2A) AND MAML2 AND menin returns zero PubMed records.
PubMed E-utilities esearch counts for KMT2A/MAML2/menin intersection queries, run 2026-09-19 · National Center for Biotechnology Information (NCBI), PubMed · PubMed (NCBI E-utilities) 2026What this evidence cannot show
A counted-absence claim and therefore only as good as the symbol set. It was run over MAML2, MEN1 and menin but not over every menin-inhibitor name, and it would miss a paper describing menin dependence without naming both genes in an indexed field. It is a statement about the indexed literature, not about what may be in someone's unpublished data.
Evidence that argues against this (1)
- Absence of a published intersection is weak evidence of absence of knowledge: menin dependence of KMT2A fusions is treated as a general property in the field, so a group testing a thymoma line might not consider the result novel enough to publish as a MAML2-specific finding. Massoth LR et al. 2020
- E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
KMT2A rearrangements were detected in paediatric metachronous parotid mucoepidermoid carcinomas arising after acute lymphoblastic leukaemia but in none of six primary paediatric or young-adult mucoepidermoid carcinomas, and KMT2A-rearranged metachronous cases had significantly worse overall survival than KMT2A-intact metachronous cases (p = 0.027).
Rearrangement of KMT2A Characterizes a Subset of Pediatric Parotid Mucoepidermoid Carcinomas Arising Metachronous to Acute Lymphoblastic Leukemia. · Othman BK, Steiner P, Leivo I, Skálová A · Fetal and Pediatric Pathology 2023What this evidence cannot show
Twelve metachronous cases against six primary controls, so the survival comparison rests on small numbers. Critically, the indexed abstract does not state which KMT2A partner was involved, and mucoepidermoid carcinoma's classical fusion is CRTC1::MAML2 with a different 5' partner - so this entry does NOT claim these tumours carry KMT2A::MAML2. Abstract read in full; the partner question could not be resolved from it.
Evidence that argues against this (1)
- Because the partner is unstated, these cases may involve any of the 100-plus KMT2A partners, and the overlap with MAML2 may be zero. Citing them as a third tissue for KMT2A::MAML2 would be a family-resemblance error, which is why the claim here is deliberately restricted to 'KMT2A-rearranged'. Nemoto N et al. 2007
the same fusion in a thymic epithelial cell: 4% of all thymomas, 6% of B2/B3 histology, median age 48
- related to →MAML2 (mastermind-like 2) - the Notch co-activator that is a KMT2A partner in leukaemia and in thymoma
MAML2 exon 2 acceptor, identical to the leukaemia junctions
co-IP of menin with the fusion from thymoma tissue, then menin-inhibitor response - never done, zero PubMed records
arm A of the three-arm natural experiment: same fusion, epithelial cell, different disease
- ← analogous toKMT2A-rearranged soft tissue sarcoma - the same gene as infant B-ALL, in a young adult's leg, as a solid tumour
the graph's other non-haematopoietic KMT2A-rearranged entity; one series found concurrent KMT2A and MAML2 rearrangement in a sarcoma case
read and not used; one sarcoma case had concurrent KMT2A and MAML2 rearrangement by FISH, an unresolved loose end