The state under menin inhibition — differentiation in AML, rapid death in ALL, and a GMP-like exit in the cells that switch lineage instead

In vitro only; no in vivo arm and no patient outcomes, so the kinetic difference is a culture observation that has not been shown to correspond to clinical response patterns. Sample numbers per arm are not given in the abstract and primary KMT2A-rearranged samples are scarce. Fusion partner is not resolved, which matters because partner distribution differs systematically between the ALL and AML arms, so a lineage difference and a partner difference are confounded by construction. Ex vivo culture of primary lymphoblasts selects strongly and short-term viability assays favour detecting death over detecting differentiation. This citation was re-fetched from PubMed for this entry rather than copied from the many existing graph entries that cite it. Read: abstract only.

• An ALL-kills/AML-differentiates dichotomy is complicated by a third outcome observed in patients rather than in culture. Profiling oncoprotein target sites across 36 MLL-rearranged samples including three that lineage-switched under therapy showed that in lineage-switching samples the oncoprotein level is REDUCED and it preferentially activates GMP genes, and in a sample that switched during revumenib treatment the oncoprotein and menin fell to undetectable levels while the cofactor ENL persisted on oncoprotein-target loci. A lymphoid blast that neither differentiates nor dies but becomes myeloid is a third exit, it occurred under this exact drug, and no in vitro viability assay of the kind used in E1 could have detected it. Read: abstract only. Janssens DH et al. 2024

VTP50469 is the tool predecessor of revumenib, not revumenib itself. The abstract names differentiation and apoptosis together without apportioning the eradication between them or separating the AML and ALL arms on that point, so this paper does not by itself establish which mechanism operates in which lineage - that is E1's contribution. Mouse xenografts in immunodeficient hosts, so no immune contribution and no differentiation syndrome. 'Select genes' is not quantified in the abstract. Read: abstract only.

• Depth of response in xenografts has not translated into comparable depth in lymphoid patients, and the class's clinical record is strongest in myeloid disease. This graph separately records that the only two complete remissions in the 51-patient adult pinometostat phase 1 were both t(11;19), on a drug that does not touch menin at all, and holds absence entries for partner-stratified and reciprocal-status-stratified response in menin inhibitor trials - meaning the clinical evidence that would test whether the lymphoid arm responds as deeply as these mice did has not been published in stratified form. A year of disease-free survival in NSG mice is a statement about a xenograft's dependence, not about a child's disease. Read: this note is an internal cross-reference to absence entries in this graph, not a claim from the cited paper; the citation is given for the xenograft result it qualifies. Krivtsov AV et al. 2019

The revumenib lineage-switch observation is a single sample, and a single patient sample profiled by CUT&Tag cannot establish that ENL persistence caused the switch rather than accompanying it. Oncoprotein enrichment is measured with antibodies against the N-terminal MLL portion in the standard configuration for this method, which detects wild-type KMT2A as well as the fusion - the attribution problem this project has audited in detail - so 'oncoprotein levels' should be read as an occupancy measurement with a known specificity limit. Three lineage-switching samples out of 36 is a small denominator for a claim about what switching samples do in general. Read: abstract only.

• The same result can be read as evidence against menin inhibitors specifically causing lineage switch. Lineage switch in KMT2A-rearranged leukaemia is documented after CD19-directed therapy and after conventional chemotherapy - a fact this note asserted without a source until 2026-09-20, when the Q40 counter-evidence quality sweep fetched one and added it as the note below - and the paper's general finding is that reduced oncoprotein level, from whatever cause, shifts preference toward GMP genes. On that reading the revumenib sample is one instance of a general dose-of-oncoprotein effect rather than a drug-class property, and menin inhibition would be no more lineage-switch-prone than any other intervention that lowers effective oncoprotein activity. Two of the three switching samples in this study did not switch on a menin inhibitor. Read: abstract only (same paper). Janssens DH et al. 2024
• INDEPENDENT SOURCE for the 'lineage switch after CD19-directed therapy' claim in the preceding note, added 2026-09-20 by the Q40 counter-evidence quality sweep. An infant with t(4;11)(q21;q23) ALL refractory to cytotoxic chemotherapy was given blinatumomab; after rapid clearance of peripheral lymphoblasts the marrow showed a lineage switch to CD19-NEGATIVE MONOBLASTIC AML, and remission followed myeloid-directed chemotherapy. This matters for the entry's argument because it is the index fusion, the index age group, and a drug that does not touch menin: it supports reading the revumenib lineage-switch observation as an instance of a general dose-of-oncoprotein or selection effect rather than a menin-inhibitor class property. Rayes A et al. 2016

Myeloid only, and the in vivo demonstration is in an NPM1-mutated rather than a KMT2A-rearranged xenograft, so the strongest in vivo evidence in the paper is for the genotype that is not this graph's subject. DS-1594b is not an approved agent. BH3 profiling is used, which makes this the closest published approach to measuring apoptotic priming under menin inhibition, but the abstract does not report a before-and-after priming result for KMT2A-rearranged cells specifically. Read: abstract only.

• A differentiation-plus-venetoclax rationale developed in AML does not transfer to the lymphoid disease, where the same drug class induces rapid cell death rather than differentiation. If the menin inhibitor is already cytotoxic in KMT2A-rearranged ALL, the mechanistic basis claimed for synergy here - menin inhibition altering anti-apoptotic regulator expression to lower the threshold for a BH3 mimetic - may be redundant or may saturate, and the combination's benefit in the lymphoid setting cannot be assumed from the myeloid result. Read: abstract only. Adriaanse FRS et al. 2024

KNOWN BUT UNREADABLE, checked 2026-09-20 by all four routes. (1) Europe PMC core record for EXT_ID:41711432 returns pmcid null, isOpenAccess N, inEPMC N. (2) and (3) fullTextXML and efetch db=pmc require a PMCID and none exists; elink pubmed to pmc returned an empty linkset and the NCBI ID converter returns 'Identifier not found in PMC'. (4) No PMC HTML article page exists to request. The PubMed record carries no abstract, and the DOI resolves to a publisher page returning HTTP 403. Only the title is verifiable. Per this project's rule nothing is inferred about which inhibitors differ or in which direction.

• This graph holds risk-menin-inhibitors-treated-as-a-class-in-infant-all, which argues that treating menin inhibitors interchangeably is unsafe. A title asserting differential in vitro sensitivity among menin inhibitors in exactly this population is the most directly relevant published item to that risk entry, and it cannot be read - so the risk entry is neither strengthened nor weakened by it, and anyone re-running this search should know the paper exists and why it is not cited for content. The counter-consideration is that in vitro potency differences among inhibitors of the same pocket are routine, are dominated by compound properties rather than by biology, and would not by themselves establish that the agents are clinically non-interchangeable. Dymock SCC et al. 2026