KMT2A::MLLT1 is high-risk in childhood AML and the best-outcome cell in childhood T-ALL: the partner effect changes sign with lineage
also called MLLT1 lineage sign flip · t(11;19)(q23;p13.3) prognosis by lineage · ENL partner prognosis
The same partner gene, MLLT1, marks the worst group in childhood myeloid leukemia and the best group in childhood T-cell leukemia. A partner effect that reverses direction depending on the cell type cannot be a simple property of the partner.
The same thing, for a scientist
KMT2A::MLLT1, arising from t(11;19)(q23;p13.3), carries opposite prognostic sign in the two lineages. In childhood AML, 19p13.3/KMT2A::MLLT1 is one of five partners in the I-BFM high-risk group, whose 5-year EFS is 30.3% against 54.0% for non-high-risk partners, with the partner group independent of MRD in multivariable analysis (EFS HR 2.0, 95% CI 1.5-2.5). In non-infant childhood ALL, t(11;19)(q23;p13.3) accounted for 106 of 629 patients (20.0%) and t(11;19)-positive T-ALL had the highest reported 5-year EFS in the entire cohort, 91.2% (+/-4.9, n=34), against a whole-cohort 69.1%. And in a 465-case cross-age B-ALL analysis, MLLT1 was the one fusion term that remained significant against a KMT2A::AFF1 reference after adjustment for age, WBC, sex and B-cell maturity (P=0.033), in the favourable direction, with MLLT1r the decision-tree split predicting fast MRD clearance among developmentally immature cases.
Why a sign flip is the most informative shape a partner effect can take
A partner effect that is uniformly adverse or uniformly favourable is compatible with the partner being a marker of something else - age, protocol, comutation. A partner effect that reverses across lineage is not: whatever the partner does, it does something different in a myeloid cell than in a T cell 1, 2. That is a positive claim about partner-specific biology and it is the single strongest argument in this beat against treating KMT2A fusions as one interchangeable class.
The honest weakness: this is a cross-study juxtaposition
No study has fitted a partner-by-lineage interaction term. The AML side comes from a 1,130-patient classification 1; the ALL side from a 34-patient T-lineage cell inside a 629-patient retrospective cohort 2. Different cohorts, different endpoints, different eras, no common model. The 91.2% figure has n=34 and the comparison was not pre-specified. The direction is supported; the interaction is not tested. That test is the cheapest decisive experiment this beat identified and is written up as hyp-partner-outcome-separation-versus-menin-class-assumption.
Band ambiguity does not explain it away
One deflationary explanation would be that t(11;19) records are contaminated by KMT2A::ELL at 19p13.1. Both of the studies above specify 19p13.3 rather than a bare t(11;19) 1, 2, so the sub-band is resolved on both sides of the flip and the ELL/MLLT1 confusion is not the cause here. It remains a live problem for series that report only t(11;19) - see concept-cytogenetic-band-versus-molecular-partner-misassignment.
What it would mean if true
MLLT1 (ENL) is a YEATS-domain reader and a core super elongation complex component. If its prognostic sign depends on lineage, the plausible mechanism is that the transcriptional programme the fusion enforces is compatible with, or lethal to, different differentiation states - which is the same variable (developmental maturity) that came out significant in the adjusted B-ALL model 3. That points at cell-of-origin as the mediator, not at menin.
| metric | prognostic direction of KMT2A::MLLT1 by lineage |
|---|---|
| value | adverse in childhood AML, favourable in childhood T-ALL and in cross-age B-ALL MRD clearance |
| unit | direction |
| population | children and adults with KMT2A::MLLT1 (t(11;19)(q23;p13.3)) leukaemia |
| interaction tested | false |
| sub band resolved | yes - both AML and ALL sources specify 19p13.3, so KMT2A::ELL at 19p13.1 is not the explanation |
| region | international |
| year | 2026 |
| prespecified | no - cross-study juxtaposition of non-pre-specified subgroups |
| source | PMIDs 36996387, 36256911, 41743263 |
cells — the numbers behind the chart
[
{
"disease": "childhood AML",
"assignment": "I-BFM high-risk partner group",
"group_efs_5y_pct": 30.3,
"comparator_efs_5y_pct": 54,
"n_cohort": 1130,
"pmid": "36996387",
"direction": "adverse",
"title": "Measurable Residual Disease and Fusion Partner Independently Predict Survival and Relapse Risk in Childhood KMT2A-Rearranged Acute Myeloid Leukemia: A Study by the International Berlin-Frankfurt-Münster Study Group.",
"authors": "van Weelderen RE, Klein K, Harrison CJ, et al.",
"venue": "J Clin Oncol",
"year": 2023,
"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."
},
{
"disease": "childhood non-infant T-ALL",
"n": 34,
"efs_5y_pct": 91.2,
"se": 4.9,
"cohort_efs_5y_pct": 69.1,
"n_cohort": 629,
"pmid": "36256911",
"direction": "favourable",
"title": "Outcomes of Childhood Noninfant Acute Lymphoblastic Leukemia With 11q23/KMT2A Rearrangements in a Modern Therapy Era: A Retrospective International Study.",
"authors": "Attarbaschi A, Möricke A, Harrison CJ, et al.",
"venue": "J Clin Oncol",
"year": 2023,
"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."
},
{
"disease": "B-ALL, 1 month to 89 years",
"endpoint": "MRD clearance",
"adjusted_p": 0.033,
"reference": "KMT2A::AFF1",
"n_cohort": 465,
"pmid": "41743263",
"direction": "favourable",
"title": "Intra-subtype heterogeneity shapes treatment response in KMT2A-rearranged ALL across all age groups.",
"authors": "Hartmann AM, Bastian L, Barz MJ, et al.",
"venue": "Hemasphere",
"year": 2026,
"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."
}
]- A menin inhibitor is being developed as a class agent for KMT2A-r leukaemia. If the same partner can be the best and the worst prognostic group depending on lineage, then a single class-level response rate is an average over populations whose biology demonstrably differs, and it will mislead in both directions.
- MLLT1-rearranged T-ALL at 91.2% EFS is a group that should probably not be enrolled in an early-phase menin trial at all; yet nothing in a KMT2A-rearranged eligibility criterion excludes them.
- If the mediating variable is developmental state rather than the partner, then a menin inhibitor's activity may track cell-of-origin, and partner-stratified reporting - the thing this beat is asking for - would still be the wrong stratifier.
- Does a partner-by-lineage interaction term reach significance in a pooled individual-patient dataset? Nobody has fitted one, and it is the decisive analysis.
- What is the 5-year EFS for t(11;19)(q23;p13.3) B-ALL, the missing cell that would separate an MLLT1 effect from a T-lineage effect?
- If MLLT1 is favourable in T-lineage and adverse in myeloid, does menin-inhibitor sensitivity track the partner or the lineage? No trial reports response by both.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In childhood KMT2A-rearranged AML, 19p13.3/KMT2A::MLLT1 is one of five partners assigned to the high-risk group, which had 5-year EFS 30.3% versus 54.0%, CIR 59.7% versus 35.2% and OS 49.2% versus 70.5% (all P<.0001) in 1,130 children, with partner group independent of end-of-induction-2 MRD (EFS HR 2.0, 95% CI 1.5-2.5, P<.0001).
Measurable Residual Disease and Fusion Partner Independently Predict Survival and Relapse Risk in Childhood KMT2A-Rearranged Acute Myeloid Leukemia: A Study by the International Berlin-Frankfurt-Münster Study Group. · van Weelderen RE, Klein K, et al. · J Clin Oncol 2023What this evidence cannot show
MLLT1 is not reported as its own curve; it is one of five partners inside a grouped arm, so its individual contribution to the 24-point gap is unknown and could be small or zero. Retrospective across many national protocols 2005-2016.
Evidence that argues against this (1)
- In a 20-patient MLL-rearranged AML series, MLLT1 and MLLT3 partners were the ones associated with better benefit from allogeneic HSCT, which is the opposite direction to the high-risk assignment and shows the assignment is not universally reproduced in adults. Burillo-Sanz S et al. 2018
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In 629 children over 1 year with 11q23/KMT2A-rearranged ALL, t(11;19)(q23;p13.3) accounted for 106 patients (20.0%) and t(11;19)-positive T-ALL had the highest reported 5-year EFS in the cohort at 91.2% (+/-4.9, n=34), against a whole-cohort 69.1% (+/-1.9) and a t(9;11) T-ALL value of 41.7% (+/-17.3, n=9).
Outcomes of Childhood Noninfant Acute Lymphoblastic Leukemia With 11q23/KMT2A Rearrangements in a Modern Therapy Era: A Retrospective International Study. · Attarbaschi A, Möricke A, et al. · J Clin Oncol 2023What this evidence cannot show
n=34 in the favourable cell; a retrospective, non-pre-specified subgroup within a cohort spanning 1995-2010 across 17 study groups. The corresponding t(11;19) B-ALL figure is not in the abstract, so it is not known whether the advantage is MLLT1-specific or T-lineage-specific. Full text not open access.
Evidence that argues against this (1)
- In the same paper the range endpoints are reported as partner-by-lineage cells rather than partner main effects, so the 91.2% could be a T-lineage effect that any partner would show in T-ALL; no t(11;19) B-ALL comparator is given to exclude that. Attarbaschi A et al. 2023
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In 465 KMT2A-rearranged B-ALL cases spanning 1 month to 89 years, MLLT1 was the only fusion term significant against a KMT2A::AFF1 reference in a multivariable model including WBC, B-cell maturity score, sex and age group (P=0.033), and MLLT1 rearrangement was the decision-tree split predicting fast MRD clearance among low-maturity cases.
Intra-subtype heterogeneity shapes treatment response in KMT2A-rearranged ALL across all age groups. · Hartmann AM, Bastian L, et al. · Hemasphere 2026What this evidence cannot show
Endpoint is MRD clearance, not survival. MLLT1 n=43 in the partner-count analysis and MRD-clearance categories were available for 97 patients, so the adjusted estimate rests on a small subset. Partner and age are strongly collinear in the cohort (MLLT1 61% paediatric versus 8% adult), which destabilises the adjusted coefficient.
Evidence that argues against this (1)
- Two infant cohorts found no partner effect on event-free survival, so an MLLT1 advantage in MRD kinetics has not been shown to become a survival advantage in the youngest patients. Ilyasova K et al. 2025
lineage flips this partner's prognostic sign, so lineage must be balanced across the arms
the lineage in which MLLT1 is a high-risk partner is also the one least likely to retain the reader domain
extends it to the adult ALL, adult AML and infant bands; bounds its sign-flip to non-infant cohorts
- related to →KMT2A::MLLT1 (MLL-ENL), t(11;19)(q23;p13.3)
MLLT1 high-risk in childhood AML, best-outcome cell in childhood T-ALL
ENL/MLLT1 prognostic direction depends on lineage
the sharpest instance of the lineage interaction
the sign flip is the observation the pooled interaction analysis would confirm or kill