Menin inhibition is a reshuffle, not a subtraction: four proteins are documented to GAIN chromatin or persist under the drug, and none of them is the fusion
also called the drug reshuffles chromatin · gains under menin inhibition · chromatin proteome rewiring
The drug is usually described as taking things off DNA. In fact several things move onto DNA when it is given - a demethylase complex, a transcription factor, a repressive mark - and one partner protein simply stays behind when the fusion goes. The one protein nobody has checked for this is the fusion itself.
The same thing, for a scientist
Four documented changes under a menin inhibitor are gains or persistences rather than losses. **(1) MLL3/4-UTX gains more than 13,000 promoter sites** in murine MLL-AF9 cells under MI-503, not explained by increased UTX expression or stability, and the gained loci acquire H3K27ac, H4K16ac and MOF; UTX is required for the induced tumour-suppressive programme [E1]. **(2) JUND gains chromatin occupancy** under menin-MLL inhibitors, because JUND binds menin through a motif in the same MLL1/2 pocket the drug occupies; JUND knockout or JNK inhibition synergises with the drug, so the gain is functionally consequential and contributes to resistance [E2]. **(3) PRC1.1 deposits H2AK119ub** at a subset of fusion targets under menin inhibition, reported as independent of fusion displacement, and loss of PRC1.1 subunits causes resistance by reactivating non-canonical menin targets including MYC [E3][E4]. **(4) ENL persists** on numerous oncoprotein-target loci in the one human sample profiled under revumenib, in which the oncoprotein and menin were undetectable [E5]. **The pattern is the finding.** Every time somebody has asked what arrives or remains under this drug, they have found something. The chromatin state under menin inhibition is not the untreated state minus menin; it is a different state with new occupants, new marks and at least one retained cofactor. **In that context, the assumption that the fusion simply disappears is the least examined proposition in the class** - and it is the only one of the five for which nobody has run the corresponding analysis.
The four gains, and what kind of evidence each is
| what gains or persists | system | drug | evidence type | functionally tested? |
|---|---|---|---|---|
| MLL3/4-UTX, >13,000 new sites | murine MLL-AF9 | MI-503 | genome-wide ChIP-seq, gains explicitly called | yes - Utx KO abolishes the induced programme |
| JUND | MLLr AML/ALL | menin-MLL inhibitors | quantitative MS plus chromatin binding | yes - JUND KO and JNK inhibition synergise |
| H2AK119ub via PRC1.1 | MLL-fusion models | menin inhibition | mark deposition, subset-restricted | yes - PRC1.1 subunit loss causes resistance |
| ENL | human patient sample | revumenib | CUT&RUN, n=1 | no |
| the fusion | - | - | never analysed | - |
Three of the four have a genetic test attached, which is why this is a mechanism entry rather than a list of curiosities.
| shown for fusion | none of the four gains was measured for a KMT2A fusion protein; ENL persistence is the closest and concerns a partner, not the oncoprotein |
|---|
gains or persistences
[
{
"factor": "MLL3/4-UTX",
"direction": "gain",
"magnitude": ">13,000 new sites",
"system": "murine MLL-AF9",
"drug": "MI-503",
"functionally_tested": true
},
{
"factor": "JUND",
"direction": "gain",
"magnitude": "not quantified in the abstract",
"system": "MLLr AML/ALL",
"drug": "menin-MLL inhibitors",
"functionally_tested": true
},
{
"factor": "H2AK119ub (PRC1.1)",
"direction": "gain",
"magnitude": "subset of fusion targets",
"system": "MLL-fusion models",
"drug": "menin inhibition",
"functionally_tested": true
},
{
"factor": "ENL",
"direction": "persistence",
"magnitude": "numerous target loci",
"system": "human patient sample",
"drug": "revumenib",
"functionally_tested": false
},
{
"factor": "KMT2A fusion",
"direction": "never analysed",
"magnitude": null,
"system": null,
"drug": null,
"functionally_tested": false
}
]- Two of the four gains are resistance mechanisms with a named genetic test, so the drug creates part of its own escape route on chromatin within days of dosing - relevant to duration-of-response expectations in paediatric trials.
- A combination chosen to deepen menin displacement does nothing about a gain; combinations should be chosen against the arriving factor, which is what the UTX-CDK4/6 and JUND-JNK results already show.
- If the drug's benefit partly depends on UTX arriving and PRC1.1 depositing, then patients whose blasts lack those machineries get displacement without silencing - full target engagement and no response - and nobody is genotyping them for it.
- Do the four gains occur at the same loci? UTX, JUND, H2AK119ub and retained ENL have never been co-mapped in one system under one drug, and whether they converge or partition is the difference between one rewiring and four.
- Does the drug-induced chromatin state resemble the untreated state of any normal cell type, or is it a state that exists nowhere in development? That distinguishes differentiation from an artificial configuration with unknown long-term behaviour in a child.
- Is there a gain that is protective rather than resistance-promoting? Three of the four are described as resistance mechanisms or tumour-suppressive programmes; a systematic gain analysis might find the drug's own efficacy partly in a gain nobody has named.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
MI-503 treatment of MLL-AF9 leukaemia cells produced a substantial increase in UTX chromatin association with more than 13,000 additional promoter-proximal binding sites, not explained by increased UTX expression or protein stability, with H3K27ac, H4K16ac and MOF increasing at those loci and UTX being required for the drug-induced activation of the tumour-suppressive programme.
A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin-MLL Inhibition. · Soto-Feliciano YM, Sánchez-Rivera FJ, Perner F, et al. · Cancer Discov 2023What this evidence cannot show
Murine MLL-AF9 cells and the tool compound MI-503; treatment 4-6 days; promoter-centric analysis at TSS +/- 2 kb. The human arms of the paper are smaller. The UTX gain is presented as a consequence of MLL1-menin displacement from promoters, which the authors report for that system.
Evidence that argues against this (1)
- Mouse fibroblasts, which are not menin-dependent, showed no UTX mobilisation under MI-503, which supports specificity but also means the gain requires a menin-dependent starting state and may not generalise to every MLLr context. Soto-Feliciano YM et al. 2023
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Menin-MLL inhibitor treatment increased JUND chromatin occupancy and upregulated JUND target genes, contributing to resistance; JUND inactivation or JNK inhibition synergised with menin-MLL inhibition in vitro and reduced tumour burden in vivo.
Menin-MLL inhibitors enhance JUND activity in MLLr leukemic cells contributing to tumorigenesis and therapy resistance. · Ozyerli-Goknar E, Nizamuddin S, Fetsch V, et al. · Blood 2026What this evidence cannot show
Chromatin binding assays described at abstract level with no stated genome-wide differential method, cell line, concentration or timepoint; the quantitative mass spectrometry of disrupted menin-JUND interactions is the paper's primary evidence. JUND competes for the same menin pocket, so this is a direct pharmacological consequence and not a general chromatin effect.
Evidence that argues against this (1)
- Because JUND binds the very pocket the drug occupies, its liberation is designed in rather than emergent, and using it as evidence that the drug reshuffles chromatin broadly overstates it. Soto-Feliciano YM et al. 2023
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Menin inhibition induces PRC1.1-dependent deposition of H2AK119ub to silence a subset of MLL-fusion-protein targets, and the authors report this as independent of MLL-fusion displacement or transcriptional repression.
DOT1L provides transcriptional memory through PRC1.1 antagonism. · Neville D, Ferguson DT, Heikamp EB, et al. · Nat Cell Biol 2026What this evidence cannot show
The paper's main subject is DOT1L-mediated transcriptional memory; the menin arm is a comparison, and the independence claim was read from the abstract-level statement rather than from the underlying panels.
Evidence that argues against this (1)
- If the H2AK119ub deposition is a consequence of progressive H3K79 methylation loss rather than of menin inhibition itself, it belongs to the DOT1L axis and its appearance under a menin inhibitor is secondary. Neville D et al. 2026
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Loss of PRC1.1 subunits such as PCGF1 or BCOR causes menin-inhibitor resistance by epigenetic reactivation of non-canonical menin targets including MYC, and MYC inhibition resensitises - establishing that the drug's transcriptional output depends on machinery arriving at chromatin rather than only on the fusion leaving it.
Epigenetic regulation of noncanonical menin targets modulates menin inhibitor response in acute myeloid leukemia. · Zhou X, Zhang L, Aryal S, et al. · Blood 2024What this evidence cannot show
Human and mouse KMT2A-rearranged AML models; the non-canonical target class is defined by bivalent menin and H2AK119ub co-occupancy in OCI-AML2, an adult KMT2A::AFDN myeloid line, three steps from infant B-lineage KMT2A::AFF1.
Evidence that argues against this (1)
- Resistance via PRC1.1 loss shows the silencing step matters but does not show the fusion stays; a cell could equally lose the fusion and fail to consolidate silencing. Krivtsov AV et al. 2019
- E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In a patient sample profiled during revumenib treatment, the oncoprotein and menin were reduced to undetectable levels while ENL, a transcriptional cofactor of the oncoprotein, persisted on numerous oncoprotein-target loci including genes in the lineage-switching programme.
MLL oncoprotein levels influence leukemia lineage identities. · Janssens DH, Duran M, Otto DJ, et al. · Nat Commun 2024What this evidence cannot show
n = 1, confounded by a concurrent lymphoid-to-myeloid lineage switch that independently reduces oncoprotein levels. This is a persistence rather than a gain, and no gain analysis was run.
Evidence that argues against this (1)
- ENL persistence in a sample where the oncoprotein is undetectable is direct evidence that fusion retention is NOT required to maintain a chromatin platform, which weakens any inference from residual target-gene activity to residual fusion occupancy. Krivtsov AV et al. 2019
two of the four documented gains show the pipeline detects gains when asked
JUND gains chromatin occupancy under the drug
UTX gains more than 13,000 promoter sites under MI-503
independent confirmation of that entry's mechanism from the gain side
the H2AK119ub gain is the third of four documented arrivals
ENL is the fourth case - persistence at target loci after the oncoprotein is undetectable
establishes that the missing fusion analysis is a choice of question, not a limit of the assay