KMT2A::MAML2, inv(11)(q21q23) - a therapy-related fusion that also causes a solid tumour
also called MLL-MAML2 · KMT2A-MAML2 · MLL::MAML2 · inv(11)(q21q23)
This fusion is made when a piece of chromosome 11 flips, joining KMT2A to MAML2. It is unusual twice over: it usually appears as a second cancer after chemotherapy for something else, and the very same fusion turns up in thymoma, a tumour of the chest.
The same thing, for a scientist
KMT2A::MAML2 arises by intrachromosomal inversion inv(11)(q21q23), joining KMT2A exon 7-11 to MAML2 exon 2 [E1][E2][E3]. The predicted protein is 1408 KMT2A N-terminal residues plus 952 MAML2 C-terminal residues, losing MAML2's NOTCH-ICD-binding MamL-1 domain and keeping its transactivation domain; in a reporter assay it suppressed NOTCH1-ICD-driven HES1 activation [E1]. It is rare in leukaemia (4 patients in 3401) but has a distinctive clinical signature: **the majority of reported leukaemia cases are therapy-related**, following cytotoxic treatment for another malignancy - secondary AML and MDS in adults [E1], secondary T-ALL in children after Ph-positive B-ALL [E2] and after hepatoblastoma [E4], T-lymphoblastic lymphoma after RUNX1::RUNX1T1 AML [E5], and B-ALL after a sarcoma [E3]. In parallel it is the first recurrent gene fusion described in type B thymoma, at 4% of thymomas and 6% of B2/B3 histology, in adults with a median age of 48 [E6]. And in one child it appeared during neuroblastoma therapy, was expressed at low level, became undetectable and produced no leukaemia over 12.8 years [E7] - the most direct evidence in this graph that a KMT2A fusion is not by itself sufficient.
The therapy-related signature
Most KMT2A fusions in this graph are de novo infant disease. This one is not. Collecting the individually reported cases:
| report | prior therapy / prior disease | resulting disease | age |
|---|---|---|---|
| Nemoto 2007 1 | prior cytotoxic therapy | secondary AML; secondary MDS | adults |
| Metzler 2008 8 | prior therapy | secondary T-ALL | adolescent |
| Mariani 2020 2 | chemotherapy for Ph-positive B-ALL | T-cell therapy-related ALL | youngest reported, preschool |
| Takahashi 2019 4 | hepatoblastoma treatment | secondary T-ALL | paediatric |
| Menu 2017 3 | sarcoma treated 2014 | B-ALL (first B-ALL case) | 47 y |
| Li 2026 5 | myeloid sarcoma and RUNX1::RUNX1T1 AML | secondary T-lymphoblastic lymphoma | paediatric |
| Tang 2014 9 | intensive chemotherapy for T-ALL | AML and therapy-related MDS, 24 and 15 months later | 12 y and 29 y |
| Felix 2021 7 | TOP2-poison regimen for high-risk neuroblastoma | no leukaemia, clone regressed | paediatric |
The consistency is striking and it has a mechanistic explanation: Felix et al. mapped enriched etoposide-induced TOP2A cleavage in the relevant MAML2 genomic region, supporting a TOP2A DNA-damage mechanism for the formation of this particular fusion 7. That is a rare case where a partner-specific breakage mechanism has actually been measured rather than assumed.
The T-lineage bias, and why it is a problem for the Notch story1 deeper
Of the leukaemia cases above, an unusual number are T-lineage: secondary T-ALL in at least three children 248, T-lymphoblastic lymphoma in one 5, and both patients in the biallelic-inversion report presented initially as T-ALL before relapsing as myeloid disease 9. One paper concludes explicitly that inv(11)(q21q23)/KMT2A-MAML2 is likely a recurrent cytogenetic abnormality in T-cell therapy-related ALL and appears associated with paediatric cases 2.
That sits badly with the mechanism. T-ALL is the lineage in which NOTCH1 is most frequently activated, and the only functional measurement of this fusion shows it suppressing Notch-driven HES1 activation 1. Either the reporter assay does not represent what the fusion does in a thymocyte, or Notch is not the operative axis in these patients, or the fusion's dominant-negative effect on Notch is tolerated because the disease is driven by the KMT2A moiety. This entry does not resolve it and does not pretend to; it is flagged as the central unexplained tension in this genotype.
A biallelic case, which is nearly unheard of
Two patients - a 12-year-old boy and a 29-year-old woman - had homozygous inv(11)(q21q23) with biallelic KMT2A rearrangement, confirmed by FISH, and MAML2 was identified as the partner in one of them. The authors attribute it to acquired uniparental disomy. Both presented as T-ALL, achieved complete remission, and recurred as AML and as therapy-related MDS at 24 and 15 months 9. In the overwhelming majority of KMT2A rearrangements only one allele is involved, so this is an outlier worth recording: it means a cell can tolerate losing both wild-type KMT2A alleles to the rearrangement, which bears on any model in which residual wild-type KMT2A matters.
Junction structure: KMT2A varies, MAML2 exon 2 almost never does
Across every report that gives a junction, the MAML2 acceptor is exon 2 - with one published exception noted below - while the KMT2A donor varies:
- MLL exon 7 to MAML2 exon 2 1
- KMT2A exon 8, 9, 10 or 11 to MAML2 exon 2, across 11 thymomas 6
- in one B-ALL, three products from the same patient: exon 7 to exon 2, exon 9 to intron 1-2, and exon 8 to exon 2 3
Every KMT2A donor listed lies within the major BCR (intron 7 - exon 13), so - unlike KMT2A::USP2 - this is an ordinary major-BCR fusion that loses the PHD fingers. The asymmetry runs the other way from the KMT2A side: five donor exons against one acceptor. It is not strictly invariant - the B-ALL patient's third product joined KMT2A exon 9 to MAML2 intron 1-2, not exon 2 3 - so the right word is strongly preferred. The same preferred acceptor and the same retained MAML2 fragment are shared with CRTC1::MAML2 in salivary-gland tumours 1. See breakpoint-maml2-exon-2-preferred-acceptor.
The same fusion in an epithelial tumour
KMT2A-MAML2 is the first recurrent gene fusion described in type B thymoma: 11 patients, 4% of all thymomas (10/242) and 6% of B2/B3 histology (10/169), median age 48 (range 29-69), 55% men, with concurrent genomic alterations infrequent 6. A paralogous KMT2A::MAML3 fusion has since been described in a type B3 thymoma, sharing the same downstream domains 10.
The existence of the same fusion in two completely different tissues, causing two completely different diseases with different age distributions, is a natural experiment about cell of origin that this graph should not let pass. It is developed in disease-kmt2a-maml2-thymoma.
Analogy: the same 5-prime gene as the index fusion, and the opposite answer on sufficiency
Closest analogue, and the axis. fusion-kmt2a-aff1, on the axis of the shared 5-prime partner. Both are KMT2A fusions; both retain the AT-hooks, CXXC and the menin-binding motif that make a KMT2A fusion menin-dependent in principle. Holding KMT2A constant is what makes the comparison worth writing, because everything that differs has to be attributed to the partner, the context or the cell.
And almost everything differs.
| KMT2A::AFF1 | KMT2A::MAML2 | |
|---|---|---|
| how it arises | de novo, in utero | majority of leukaemia cases are therapy-related, after cytotoxic treatment for another malignancy 1245 |
| lineage | B-lineage infant ALL | T-lineage biased in children, secondary AML/MDS in adults, one B-ALL 2345 |
| frequency | the commonest infant KMT2A partnership | 4 patients in 3401 |
| outside haematopoiesis | none | the first recurrent gene fusion described in type B thymoma, 4% of thymomas and 6% of B2/B3 histology 6 |
| sufficiency | close to sufficient in a fetal progenitor - near-unity twin concordance | demonstrably insufficient: in one child it emerged during neuroblastoma therapy, was expressed at low level, became undetectable and produced no leukaemia over 12.8 years 7 |
What the analogy predicts, and where the test came from. If a KMT2A fusion were sufficient by virtue of being a KMT2A fusion, a detectable KMT2A::MAML2 clone should progress. It did not 7. This is the most direct evidence in this graph that a KMT2A fusion is not by itself sufficient, and it is exactly the observation the infant twin-concordance data cannot supply, because those data are about a fusion that almost always does progress. The pair therefore brackets the question: same 5-prime gene, near-unity penetrance at one end and a spontaneously clearing clone at the other.
Where it breaks, and the break is the content. Four variables move together between the two cases and none of them is isolated:
- the partner - MAML2 supplies a NOTCH-coactivator transactivation domain and, in a reporter assay, suppressed NOTCH1-ICD-driven HES1 activation 1, which is not the elongation-complex recruitment AFF1 supplies;
- the cell - a fetal B-lineage progenitor against whatever cell is cycling in a child receiving neuroblastoma chemotherapy;
- the expression level - the clearing clone was expressed at low level 7, and a fusion below some threshold is not the same experiment as a fusion at physiological levels;
- the context - a therapy-damaged marrow under selection is not a developing fetus.
So the honest reading is not 'KMT2A::MAML2 shows KMT2A fusions are insufficient'. It is: at least one KMT2A fusion, in at least one cell, at low expression, was insufficient - which is enough to refute a universal sufficiency claim and not enough to say what the missing ingredient is. The candidate that the T-lineage bias points at is the cell: this fusion appears in T-lineage disease where KMT2A::AFF1 essentially never does.
A second axis worth naming: the same fusion in an epithelial tumour. KMT2A::MAML2 in type B thymoma 6 puts this entry alongside fusion-etv6-ntrk3, which recurs in congenital fibrosarcoma, cellular mesoblastic nephroma and secretory breast carcinoma. Both are cases where one fusion and several unrelated tissues make the cell of origin, not the oncoprotein, the variable that sets the disease.
| gene5 | KMT2A |
|---|---|
| gene3 | MAML2 |
| cytoband | inv(11)(q21q23) |
| mechanism class | intrachromosomal inversion; MAML2 at 11q21, KMT2A at 11q23. Etoposide-induced TOP2A cleavage is enriched in the relevant MAML2 genomic region, supporting a TOP2A DNA-damage mechanism. |
| uniprot5 | Q03164 |
| uniprot3 | Q8IZL2 |
| uniprot3 verified | Q8IZL2 = MAML2_HUMAN, PRIMARY gene name MAML2, 1156 aa, Homo sapiens (UniProt REST, fetched 2026-09-19; primary gene name and length read back from the record). |
| prognosis | Not estimable for the leukaemia. Every leukaemia report is a single case or a pair, treatment varies, and several patients had a prior malignancy that dominates their prognosis. In thymoma the fusion marks the B2/B3 subtypes, which are the more aggressive histologies, but no survival comparison against fusion-negative B2/B3 thymoma is published. |
| therapy related fraction | The large majority of reported leukaemia cases followed cytotoxic therapy for a prior malignancy: Ph-positive B-ALL, hepatoblastoma, sarcoma, neuroblastoma, RUNX1::RUNX1T1 AML and T-ALL are all documented antecedents. |
diseases
[ "therapy-related secondary AML", "therapy-related MDS", "therapy-related T-ALL (paediatric)", "T-lymphoblastic lymphoma (secondary)", "B-ALL (one adult case, post-sarcoma)", "type B2/B3 thymoma" ]
frequency
{
"dcal_recombinome_n_2023": 4,
"individually_reported_leukaemia_cases": "at least 8 across 7 reports",
"thymoma_frequency_pct_all": 4,
"thymoma_frequency_pct_b2_b3": 6,
"pubmed_records_on_intersection_raw": 21,
"pubmed_records_title_checked": 15,
"note": "The recombinome count (4) is far below the published case count, plausibly because therapy-related disease in adults is diagnosed outside the paediatric networks that refer to DCAL."
}breakpoints
[
{
"id": "bp-kmt2a-exon7-11-maml2-exon2",
"gene5_exon_last": 7,
"gene3_exon_first": 2,
"population": "KMT2A exon 7 to MAML2 exon 2 in the founding secondary AML/MDS cases; KMT2A exon 8, 9, 10 or 11 to MAML2 exon 2 across 11 thymomas; one B-ALL showed exon 7 to exon 2, exon 9 to intron 1-2 and exon 8 to exon 2 in the same patient. Every KMT2A donor lies within the MAJOR BCR (intron 7 - exon 13).",
"domains_retained_5": [
"AT-hook 1",
"AT-hook 2",
"AT-hook 3",
"SNL1/2",
"MBM1",
"MBM2",
"CXXC"
],
"domains_lost_5": [
"PHD1",
"PHD2",
"PHD3",
"Bromodomain",
"PHD4",
"FYRN",
"TAD",
"FYRC",
"WIN",
"SET"
],
"domains_retained_3": [
"TAD (transcriptional activation domain)"
],
"domains_lost_3": [
"MamL-1 (mastermind-like N-terminal basic domain; binds NOTCH ICD on CSL)"
],
"phenotype_notes": "Predicted protein 1408 KMT2A residues + 952 MAML2 residues, i.e. MAML2 residues ~205-1156. Losing MamL-1 (33-87) and keeping the TAD (609-681) predicts a Notch dominant-negative, which the founding report measured on a HES1 reporter. The MAML2 exon 2 acceptor is strongly preferred but not strictly invariant: one B-ALL patient also produced a KMT2A exon 9 to MAML2 intron 1-2 junction."
}
]never measured
[ "subcellular and subnuclear localisation of the fusion protein", "any epigenetic readout in leukaemia or thymoma", "HOXA9/MEIS1 induction", "menin dependence in either tissue", "any cell line, mouse model or xenograft" ]
- This fusion is largely iatrogenic. Every therapy-related case is a consequence of curing something else, and the TOP2A cleavage mapping ties it specifically to topoisomerase-II-poison exposure - so it is a direct cost of etoposide-containing regimens that will not be reduced by any KMT2A-directed drug.
- The obvious Notch-directed drug class, gamma-secretase inhibitors, would reduce Notch signalling - the same direction the fusion's measured activity already points. Choosing a Notch inhibitor on the basis that the partner is a Notch co-activator could be precisely backwards.
- The same fusion causes an indolent-to-aggressive epithelial thymoma in middle-aged adults and an acute leukaemia in children. Any therapeutic developed against the fusion protein will have to work in two cell states that could not be more different, and success in one says nothing about the other.
- Why is this fusion T-lineage-biased in leukaemia when its only measured activity is suppression of Notch, the pathway T-ALL usually activates? Nothing in the literature addresses the contradiction.
- Is KMT2A::MAML2 menin-dependent? It is a major-BCR fusion retaining MBM1 and MBM2, so on the graph's own model it should be - and zero PubMed records connect this fusion to menin in either leukaemia or thymoma.
- The recombinome counts 4 patients while the case literature describes at least 8. Is KMT2A-MAML2 systematically under-referred because it presents as a second malignancy in adults rather than as infant leukaemia?
- Does the biallelic inv(11) case mean a cell can dispense with wild-type KMT2A entirely? If so it bears directly on models in which residual wild-type KMT2A constrains the fusion.
- Is KMT2A::MAML2 menin-dependent? It retains the menin-binding motif like every other KMT2A fusion, so on hyp-menin-dependency-tracks-available-mbm it should be sensitive - but it is T-lineage biased, mostly therapy-related, and has never been tested with any menin inhibitor in any system. It is also the one KMT2A fusion with a documented spontaneously clearing clone, which makes it the natural place to ask whether menin dependence tracks the fusion or the cell: a menin-inhibitor sensitivity measurement on a KMT2A::MAML2 T-ALL sample would test the motif model outside B-lineage myeloid-adjacent disease for the first time.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
MLL exon 7 fused to MAML2 exon 2 in secondary AML and MDS with inv(11)(q21q23), producing a predicted 1408 + 952 residue protein that deletes MAML2's NOTCH-ICD-binding basic domain, shares its C-terminal MAML2 portion with MECT1-MAML2, and suppressed NOTCH1-ICD-driven HES1 promoter activation in a luciferase assay.
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 adult patients. The luciferase experiment uses a single reporter promoter in a transfected line, not endogenous Notch targets in a leukaemia cell, and the fusion protein itself was never detected - the residue counts are predicted from the chimeric transcript. Abstract read in full; figures not re-derived.
Evidence that argues against this (1)
- Several later cases of this fusion are T-lineage, the lineage in which Notch is characteristically activated rather than suppressed, which is hard to reconcile with a dominant-negative-Notch mechanism measured on one reporter. Mariani RA et al. 2020
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
A T-cell therapy-related ALL with inv(11)(q21q23) involving KMT2A and MAML2 arose after chemotherapy for Philadelphia-chromosome-positive B-ALL; the authors describe this as the youngest such patient, the first independent report following an initial series also in children, and conclude the fusion is likely a recurrent cytogenetic abnormality in T-cell therapy-related ALL associated with paediatric cases.
Inv(11)(q21q23); KMT2A-MAML2, a Recurrent Genetic Abnormality in T-Cell Therapy-related Acute Lymphoblastic Leukemia. · Mariani RA, Silva M, Caparelli E, Jennings LJ, Yap KL, Leuer KM, Weinstein J, Gong S · Journal of Pediatric Hematology/Oncology 2020What this evidence cannot show
A single case report; 'recurrent' rests on this case plus a prior small series. Prior therapy for Ph-positive B-ALL included a tyrosine-kinase inhibitor as well as cytotoxics, so the initiating exposure is not isolated. No functional work. Abstract read in full.
Evidence that argues against this (1)
- The same fusion also occurs in de novo-appearing B-ALL and in thymoma with no leukaemic context, so 'recurrent abnormality in T-cell therapy-related ALL' describes a subset of its behaviour rather than the fusion's defining property. Massoth LR et al. 2020
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
The first B-ALL case with a KMT2A-MAML2 rearrangement was a 47-year-old woman with inv(11)(q21q23) previously treated for a sarcoma; RNA sequencing detected junctions of KMT2A exon 7 to MAML2 exon 2 and exon 9 to MAML2 intron 1-2, and Sanger sequencing a junction of exon 8 to exon 2; prior literature at the time comprised four myeloid neoplasms after chemotherapy (two AML, two MDS) and two secondary T-ALL.
First case of B ALL with KMT2A-MAML2 rearrangement: a case report. · Menu E, Beaufils N, Usseglio F, Balducci E, Lafage Pochitaloff M, Costello R, Gabert J · BMC Cancer 2017What this evidence cannot show
A single patient. Three different junctions were detected in the same case by two methods, which may reflect alternative splicing, subclonal heterogeneity or technical artefact - the paper does not resolve which, and this matters for any claim that the junction is stereotyped. Abstract read in full.
Evidence that argues against this (1)
- Three distinct junctions in one patient argues against reading the exon-7-to-exon-2 structure as a fixed rule on the KMT2A side, and the thymoma series independently found four different KMT2A donor exons. Only the MAML2 exon 2 acceptor is stable across reports. Massoth LR et al. 2020
- E4weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper
A paediatric case of secondary T-cell acute lymphoblastic leukaemia with KMT2A-MAML2 developed after treatment for hepatoblastoma.
A pediatric case of secondary T-cell acute lymphoblastic leukemia with KMT2A-MAML2 developing after hepatoblastoma treatment. · Takahashi Y, Terui K, Chinen Y, Tandai S, Kudo K, Sasaki S, Tono C, Taki T, Ito E · Pediatric Blood & Cancer 2019What this evidence cannot show
A Letter with no indexed abstract, so only the title-level claim is carried here and the body was not read. One patient. No junction, outcome or mechanistic detail is available to this entry.
Evidence that argues against this (1)
- Hepatoblastoma regimens are platinum- and anthracycline-based rather than dominated by epipodophyllotoxins, so this case does not straightforwardly fit the etoposide/TOP2-poison model that the neuroblastoma study supports for this fusion. Felix CA et al. 2021
- E5weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper
A secondary T-lymphoblastic lymphoma with KMT2A::MAML2 rearrangement has been reported following myeloid sarcoma and RUNX1::RUNX1T1-positive acute myeloid leukaemia.
Secondary T-Lymphoblastic Lymphoma With KMT2A::MAML2 Rearrangement Following Myeloid Sarcoma and RUNX1::RUNX1T1-Positive Acute Myeloid Leukemia. · Li T, Wang A, Wu P, Sun H, Zhang L, Chen M, Zhao X, Wang H · Pediatric Blood & Cancer 2026What this evidence cannot show
A Letter with no indexed abstract; only the title-level claim is carried and the body was not read. One patient. Whether the KMT2A::MAML2 clone was therapy-induced or pre-existing cannot be determined from the title alone.
Evidence that argues against this (1)
- A single title-level case cannot be weighed against the cohort literature, and a report in which two fusion oncoproteins occur sequentially in one patient raises the possibility of an underlying predisposition or a shared exposure that neither this entry nor the source addresses. Felix CA et al. 2021
- E6strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
KMT2A-MAML2 is the first recurrent gene fusion described in type B thymoma: 11 fusion-positive patients, breakpoints between KMT2A exon 8, 9, 10 or 11 and MAML2 exon 2, 55% men, median age 48 (range 29-69), infrequent concurrent genomic alterations, B2 or B3 histology, 4% of all thymomas (10/242) and 6% of B2/B3 (10/169).
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 thymoma denominator is enriched for advanced or refractory disease; only a portion of samples had RNA profiling, so detection was not uniform. Eleven fusion-positive patients in total but 10 within the 242-thymoma denominator, which is why the two numbers differ. No functional work and no treatment data. Abstract read in full.
Evidence that argues against this (1)
- A paralogous KMT2A::MAML3 fusion has since been reported in type B3 thymoma with the same downstream domains, so the recurrent thymoma lesion is a KMT2A-MAML-family fusion and a MAML2-keyed frequency is a floor rather than the true rate. Zhou Z et al. 2025
- E7strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Among 12 patients followed after TOP2-poison chemotherapy in a high-risk neuroblastoma regimen, one harboured an inv(11) KMT2A rearrangement expressing a low-level KMT2A-MAML2 transcript; the inv(11) was undetectable in subsequent samples and no leukaemia developed over 12.8 years of follow-up, with enriched etoposide-induced TOP2A cleavage in the relevant MAML2 genomic region supporting a TOP2A DNA-damage mechanism.
KMT2A-MAML2 rearrangement emerged and regressed during neuroblastoma therapy without leukemia after 12.8-year follow-up. · Felix CA, Slater DJ, Davenport JW, Yu X, Gregory BD, Li MM, Rappaport EF, Cheung NV · Pediatric Blood & Cancer 2021What this evidence cannot show
One patient with the rearrangement out of twelve studied. 'Undetectable' is bounded by assay sensitivity - a clone below the detection floor is not a clone that is gone - and clonal extinction cannot be distinguished from suppression below threshold. The TOP2A cleave-ome mapping is done on the MAML2 genomic region in a model system, not in the patient's own cells. Abstract read in full.
Evidence that argues against this (1)
- Other patients with this exact fusion did develop leukaemia after cytotoxic therapy, in several independent reports, so regression in one child does not generalise. The informative comparison is why this clone regressed when others did not, and the study has no answer. Mariani RA et al. 2020
- E8moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
inv(11)(q21q23) fuses MLL to the Notch co-activator mastermind-like 2 in secondary T-cell acute lymphoblastic leukaemia, in an adolescent male who underwent haematopoietic stem-cell transplantation.
Inv(11)(q21q23) fuses MLL to the Notch co-activator mastermind-like 2 in secondary T-cell acute lymphoblastic leukemia. · Metzler M, Staege MS, Harder L, Mendelova D, Zuna J, Fronkova E, Meyer C, Flohr T, Bednarova D, Harbott J, Langer T, Gesk S, Trka J, Siebert R, Dingermann T, Marschalek R, Niemeyer C, Rascher W · Leukemia 2008What this evidence cannot show
A Letter with no indexed abstract; the claim is carried at title level plus the MeSH-indexed clinical context (adolescent, male, second primary neoplasm, HSCT, disease-free survival). The body was not read, so no junction, no functional data and no follow-up duration are available to this entry.
Evidence that argues against this (1)
- Describing MAML2 as 'the Notch co-activator' in the title frames the fusion's mechanism as Notch-related, but the fusion loses MAML2's Notch-binding domain and the only functional assay shows Notch suppression. The title's framing should not be taken as a mechanistic finding. Nemoto N et al. 2007
- E9moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Two patients - a 12-year-old boy and a 29-year-old woman - had homozygous inv(11)(q21q23) with biallelic MLL rearrangement confirmed by FISH, likely from acquired uniparental disomy; MAML2 was the identified partner in one; both presented as T-lymphoblastic leukaemia/lymphoma, achieved complete remission, and recurred as AML and as therapy-related MDS at 24 and 15 months respectively.
Homozygous inv(11)(q21q23) and MLL gene rearrangement in two patients with myeloid neoplasms. · Tang G, Lu X, Wang SA, Roney EK, Zhang L, Hu S, Lu G, Medeiros LJ, Patel A · International Journal of Clinical and Experimental Pathology 2014What this evidence cannot show
Two patients, and MAML2 was confirmed as the partner in only one of them - the other is an inv(11)(q21q23) with an unidentified partner, so counting both as KMT2A-MAML2 would be wrong. The journal has no DOI for this article and it is indexed by PMID and PMC only. Abstract read in full.
Evidence that argues against this (1)
- Only one of the two patients has a confirmed MAML2 partner, so the biallelic observation rests on n = 1 for this specific fusion. Acquired uniparental disomy is also a late clonal-evolution event in many contexts, so it may be a feature of the relapsed clone rather than of the founding lesion. Nemoto N et al. 2007
- E10moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
A novel KMT2A::MAML3 fusion has been reported in an invasive type B3 thymoma; MAML3 and MAML2 are paralogues, the fusion sites at exon 2 share similar functional protein domains, and the same domain appears downstream of the KMT2A::MAML2 fusion protein.
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
A single case report. DNA-based NGS found no pathogenic variants and the fusion was detected only by RNA sequencing. The authors' conclusion that MAML3 fusions lead to abnormal Notch signalling is explicitly labelled a hypothesis and was not tested. Abstract read in full.
Evidence that argues against this (1)
- One case cannot establish that MAML3 fusions are recurrent in thymoma, and the domain-sharing argument is a sequence comparison, not a functional demonstration. Treating MAML3 as equivalent to MAML2 on this basis would extend a 11-patient finding on the strength of a single sample. Massoth LR et al. 2020
- part of →KMT2A / MLL1 — the gene that breaks
KMT2A exon 7-11, i.e. a MAJOR-BCR fusion: AT-hooks, MBM1/2 and CXXC retained, PHD fingers lost
MAML2 exon 2 onward, ~residues 205-1156: transactivation domain retained, MamL-1 Notch-binding domain lost
every reported KMT2A donor exon (7, 8, 9, 10, 11) lies inside the major BCR - explicitly NOT a minor-BCR fusion
secondary AML and MDS after cytotoxic therapy, in the founding report
therapy-related T-ALL in several children and one adult B-ALL after sarcoma
both are intrachromosomal inversions on chromosome 11, but MAML2 breaks in the MAJOR BCR and loses the PHD fingers while USP2 breaks in the minor BCR and keeps them
- related to →RUNX1::RUNX1T1 (AML1-ETO), t(8;21)(q22;q22)
one reported patient developed KMT2A::MAML2 T-lymphoblastic lymphoma after RUNX1::RUNX1T1 AML and myeloid sarcoma
- ← related toKMT2A::MAML2 keeps MAML2's activation domain and loses its Notch-binding domain, and suppresses Notch output
the only functional measurement of this fusion: suppression of NOTCH1-ICD-driven HES1 activation, from one 2007 reporter assay
KMT2A donor varies across exons 7-11; the MAML2 acceptor does not vary
- ← arises inKMT2A::MAML2 type B2/B3 thymoma - the same fusion, a different organ, a different disease
the same fusion in a thymic epithelial cell: 4% of all thymomas, 6% of B2/B3 histology, median age 48
- ← related toA child who made a KMT2A fusion during chemotherapy, lost it again, and never got leukaemia in 12.8 years
the fusion arose during TOP2-poison therapy, was expressed, became undetectable, and caused no leukaemia in 12.8 years
- analogous to →KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)
AXIS: SHARED 5-PRIME PARTNER, OPPOSITE ANSWER ON SUFFICIENCY. Both retain KMT2A's AT-hooks, CXXC and menin-binding motif. KMT2A::AFF1 is de novo, in utero, B-lineage and close to sufficient in a fetal progenitor; KMT2A::MAML2 is mostly therapy-related, T-lineage biased in children, also causes an epithelial tumour (4% of type B thymomas), and in one child emerged during neuroblastoma therapy, was expressed at low level, became undetectable and produced no leukaemia over 12.8 years. That is the graph's most direct evidence that a KMT2A fusion is not by itself sufficient. DISANALOGY CAVEAT: partner, cell, expression level and therapy context all move together, so the case refutes a universal sufficiency claim without identifying the missing ingredient.
- analogous to →ETV6::NTRK3 (ETV6-TRKC), t(12;15)(p13;q25)
AXIS: ONE FUSION, SEVERAL UNRELATED TISSUES. KMT2A::MAML2 causes leukaemia and is the first recurrent gene fusion described in type B thymoma; ETV6::NTRK3 causes congenital fibrosarcoma, cellular mesoblastic nephroma and secretory breast carcinoma. In both, the tissue outcome is set by the cell the fusion lands in rather than by the oncoprotein. DISANALOGY: ETV6::NTRK3's cross-tissue recurrence is frequent and drugged, while KMT2A::MAML2's is rare and its two contexts differ in whether the lesion is therapy-related.
Same 5-prime gene as the index fusion and the opposite answer on sufficiency: a KMT2A::MAML2 clone emerged during neuroblastoma therapy, was expressed at low level, became undetectable and produced no leukaemia over 12.8 years.