MYC reactivation through PRC1.1 loss — a named, druggable bypass out of menin dependence
also called PRC1.1 loss resistance · PCGF1 BCOR loss · non-canonical menin targets · MYC bypass
Menin inhibitors work by shutting off a set of genes. Some leukemias delete a different piece of machinery, PRC1.1, which lets them switch a second, hidden set of genes back on, including MYC. The cancer then runs on that hidden set instead, and the drug becomes irrelevant.
The same thing, for a scientist
Systematic chromatin-focused CRISPR screens in human and mouse KMT2A-rearranged AML identified a group of non-canonical menin targets that are bivalently co-occupied by active menin and repressive H2AK119ub marks and are normally downregulated after menin inhibition. Loss of PRC1.1 subunits PCGF1 or BCOR causes menin-inhibitor resistance by epigenetically reactivating these non-canonical targets, including MYC. Genetic or pharmacological MYC inhibition resensitises PRC1.1-deficient cells, and these cells show reduced monocytic gene signatures, become BCL-2-dependent, and are resensitised to menin inhibition by venetoclax. This is the best-characterised bypass programme in the disease and, unusually, it comes with two ready-made countermeasures.
The mechanism, and why it is elegant1 deeper
Menin inhibition works because menin holds the KMT2A fusion at a defined set of loci — HOXA9, MEIS1 and their neighbours — and evicting it shuts that program down.
What the screens revealed is a second class of menin-occupied loci: genes bivalently co-occupied by active menin and by repressive H2AK119ub, the mark laid down by PRC1. In a normal drug response these non-canonical targets go down along with everything else. But if PRC1.1 is lost (deletion of PCGF1 or BCOR), the repressive arm disappears, and those loci are epigenetically reactivated — including MYC 1.
The leukemia therefore escapes not by restoring the canonical program but by switching to a different one that menin was also sitting on. The drug still evicts menin from HOXA9. It simply no longer matters.
This is the clearest mechanistic instance of the general principle in this beat: the fusion's program has more than one output, and blocking the obligate partner blocks only the outputs that partner actively maintains.
Two countermeasures, both already available
Unusually for a resistance mechanism, this one arrives with its own solutions 1:
- MYC inhibition — genetic or pharmacological — resensitises PRC1.1-deficient cells to menin inhibition. MYC is not directly druggable, but it is indirectly druggable through CDK9 (MYC has a very short half-life and collapses under transcriptional pause) and through BET inhibition.
- Venetoclax — PRC1.1-deficient cells show reduced monocytic signatures and are consequently BCL-2-dependent, and venetoclax overcomes their menin-inhibitor resistance. This is mechanistically satisfying: monocytic differentiation is the canonical venetoclax-resistance state in AML, so a resistance mechanism that blocks monocytic differentiation necessarily creates venetoclax sensitivity.
That second point converts venetoclax from a generic combination partner into a mechanism-matched one, and it is the strongest single argument for the menin-plus-venetoclax regimens now in phase 3.
The CDK9 route has independent support in this disease: enitociclib lowers MYC and MCL-1 protein in KMT2A-rearranged infant leukemia cells, synergises with menin inhibitors, and potentiates venetoclax in venetoclax-resistant KMT2A-rearranged cells 2.
What is not known, and why it matters for infants
BCOR is already a node in this graph (gene-bcor), and BCOR alterations are recurrent in paediatric leukemia. But:
- Nobody has reported PCGF1 or BCOR status in patients failing menin inhibitors. The mechanism is defined in screens and models; its clinical frequency is unmeasured.
- No infant data exist at all. Whether PRC1.1 loss occurs in KMT2A-rearranged infant ALL, and whether it arises under treatment, is unknown.
- The prediction is testable and cheap. If a child on a menin inhibitor relapses with PRC1.1 loss and MYC reactivation, venetoclax should work. That is a one-patient, one-assay hypothesis that the paediatric menin trials could answer as a correlative endpoint if anyone asked them to.
| kind | resistance |
|---|---|
| mechanism class | epigenetic bypass programme |
| chromatin signature | non-canonical menin targets bivalently co-occupied by active menin and repressive H2AK119ub |
| seen in patients | false |
| seen in models | true |
| resulting phenotype | reduced monocytic gene signature, MYC reactivation, BCL-2 dependence |
| biomarker | PCGF1/BCOR loss plus reduced monocytic signature; directly measurable and never reported in a menin-inhibitor-treated patient |
affects
[ "drug-revumenib", "drug-ziftomenib", "drug-bleximenib", "drug-enzomenib", "drug-icovamenib" ]
genes
[ "PCGF1", "BCOR", "MYC" ]
countermeasures
[
{
"agent": "venetoclax",
"rationale": "reduced monocytic signature creates BCL-2 dependence; demonstrated to resensitise PRC1.1-deficient cells",
"tier": "preclinical, strong"
},
{
"agent": "MYC inhibition (genetic or indirect)",
"rationale": "MYC is the reactivated effector; inhibition resensitises",
"tier": "preclinical, strong but no direct clinical MYC inhibitor"
},
{
"agent": "CDK9 inhibition (enitociclib)",
"rationale": "collapses short-half-life MYC and MCL1; synergises with menin inhibition in KMT2A-rearranged infant cells",
"tier": "preclinical, inferred link"
},
{
"agent": "BET inhibition",
"rationale": "MYC super-enhancer dependence",
"tier": "preclinical, and limited by BRD4 common-essentiality"
}
]- Bypass by design: the fusion program has outputs that menin occupies but does not actively maintain, so evicting menin cannot switch all of them off — this is a structural limit of the interface strategy, not a fixable drug property.
- Silent biomarker: PRC1.1 loss would be visible on a standard myeloid panel (BCOR) and nobody is looking for it in menin-treated patients, so this mechanism could be common and undetected.
- Countermeasure conflict: the countermeasure is venetoclax, which is now being combined with menin inhibitors frontline — which means the combination trials may be masking this mechanism rather than revealing it, and its true frequency will become harder to measure, not easier.
- MYC undruggability: the effector at the end of this bypass is the one oncogene the field has never been able to drug directly, so every countermeasure is indirect and inherits its own resistance.
- Essential-function toxicity of the countermeasures: CDK9 and BRD4 are both common-essential, so the agents best placed to collapse MYC are the ones with the worst therapeutic index in an infant.
- How often do patients failing menin inhibitors actually have PRC1.1 loss? The mechanism is beautifully characterised in screens and has never been looked for in a patient, which is an immediately fixable gap.
- Does PRC1.1 loss occur in KMT2A-rearranged infant ALL? BCOR alterations are recurrent in paediatric leukemia but the infant KMT2A-rearranged subgroup has an exceptionally low mutation burden, so this may be an adult-AML-specific route.
- Is 'reduced monocytic signature predicts venetoclax sensitivity' usable as a prospective biomarker? It would convert a transcriptomic readout into a treatment decision at relapse, which is the sort of thing this graph exists to identify.
- Are there other non-canonical menin targets beyond MYC that could be reactivated by loss of different repressors? The screens found one route; the bivalent-target class is larger than one gene.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Systematic chromatin-focused CRISPR screens in human and mouse KMT2A-rearranged AML models identified non-canonical menin targets bivalently co-occupied by active menin and repressive H2AK119ub marks that are normally downregulated after menin inhibition; loss of PRC1.1 subunits PCGF1 or BCOR causes menin-inhibitor resistance by epigenetically reactivating these targets including MYC, genetic or pharmacological MYC inhibition resensitises the cells, and PRC1.1-deficient cells show reduced monocytic signatures, are susceptible to BCL-2 inhibition, and are resensitised to menin inhibition by venetoclax.
Epigenetic regulation of noncanonical menin targets modulates menin inhibitor response in acute myeloid leukemia · See PubMed record PMID 39158067 for the full author list (not transcribed here) · Blood 2024What this evidence cannot show
Entirely preclinical: CRISPR screens plus human and mouse AML models. No patient with menin-inhibitor resistance has been reported with PRC1.1 loss, so the clinical frequency of this mechanism is unknown and may be low. The models are AML; no KMT2A-rearranged ALL or infant data. 'Pharmacological MYC inhibition' in this context means indirect approaches, since MYC has no direct clinical inhibitor.
Evidence that argues against this (1)
- PRC1.1 loss is a screen-derived mechanism that has not been shown to be the clinical one. The resistance alteration actually recovered from patients on menin inhibitors is somatic MEN1 mutation at the drug-protein interface, which restores chromatin occupancy of menin and MLL1 without needing any MYC reactivation; and an independent line of work locates a major share of failure in PRIMARY resistance overcome by KAT6/KAT7 inhibition rather than in PRC1.1 loss. No published patient series has reported PCGF1 or BCOR loss arising under menin-inhibitor pressure. Perner F et al. 2023
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
The CDK9 inhibitor enitociclib decreases MYC and MCL-1 protein in KMT2A-rearranged leukemia cells, synergises with menin inhibitors to reduce HOXA9 protein in KMT2A-rearranged infant leukemia cells, and potentiates venetoclax cytotoxicity in relatively venetoclax-resistant KMT2A-rearranged cells.
Targeting CDK9 inhibits the growth of KMT2A-rearranged infant leukemia and demonstrates synergy with menin inhibition · See PubMed record PMID 40979068 for the full author list (not transcribed here) · Blood Neoplasia 2025What this evidence cannot show
In vitro only; the authors describe measurable in vitro antitumour activity and propose future trials. The MYC reduction was not tested specifically in PRC1.1-deficient, menin-resistant cells, so the link between this agent and this resistance mechanism is inferred rather than demonstrated.
Evidence that argues against this (1)
- Lowering MYC protein in cells has already been achieved in patients without producing remissions, which bounds what the enitociclib synergy predicts clinically. In the voruciclib phase 1, CDK9 inhibition in treated patients downregulated MYC and NF-kB transcriptional gene sets, decreased MCL1 messenger RNA and reduced RNA polymerase II phosphorylation — the exact pharmacodynamic chain this entry invokes — yet among 21 patients with AML only one reached a morphologic leukaemia-free state and two had stable disease. A CDK9 inhibitor that hits MYC and MCL-1 is not thereby an active drug, and the synergy argument has to explain why the menin-inhibitor partner would convert an inactive backbone into an active one. Davids MS et al. 2025
- E3weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.review
MYC is one of the principal proposed bypass oncogenes in KMT2A-rearranged leukemia, alongside DOT1L, BRD4 and c-MYB, and combination strategies targeting it are proposed to overcome menin-inhibitor resistance.
Synergistic Strategies for KMT2A-Rearranged Leukemias: Beyond Menin Inhibitor · See PubMed record PMID 39682203 for the full author list (not transcribed here) · Cancers (Basel) 2024What this evidence cannot show
A REVIEW used only as a map of what the field proposes; it contributes no primary data and none of its proposals should be treated as evidence. Included here to record the shape of the field's thinking, not to support any specific claim.
Evidence that argues against this (1)
- The bypass-oncogene framing assumes resistance has an identifiable single driver, and the most direct patient-derived test of that assumption failed to find one. In serially sampled xenografts from multiply relapsed KMT2A::AFF1 ALL, later samples had lost menin-inhibitor sensitivity while canonical menin-inhibitor target genes remained suppressed; RAS-pathway and TP53 co-mutations emerged, but NEITHER was sufficient to induce resistance in vitro, and the mechanism implicated in one patient was downregulation of KMT2D with selection of KMT2C-edited cells under menin-inhibitor pressure. That is a loss-of-methyltransferase route, not a MYC/DOT1L/BRD4/MYB bypass, and it arose without any menin-inhibitor exposure. A review's list of candidate bypass oncogenes should not be carried as a description of what actually drives clinical resistance. Mahdavi L et al. 2026
predicts the residual occupancy set is enriched for the non-canonical bivalent targets that drive MYC bypass
PRC1.1 bypass as a third route with its own countermeasure
PRC1.1-deficient cells being venetoclax-sensitive is the main counter-evidence
- confers resistance to →Revumenib (SNDX-5613, Revuforj) — first approved menin–KMT2A interface inhibitor
a bypass programme that keeps the cell going once the fusion program is blocked
the reactivated non-canonical menin targets are defined by bivalent menin/H2AK119ub occupancy
arm 3 is the locus-level version of the published whole-cell PRC1.1 resistance epistasis
model A rests on the PRC1.1-gated non-canonical menin target genetics recorded there
reframes that resistance route as a failure of the drug's own effector arm rather than a bypass around it
the venetoclax countermeasure named there is reported not to work in TP53-mutant cells
rival non-canonical-target account of the same clinical failure, implying the opposite countermeasure
pre-existing entry audited and not duplicated
Counter-evidence (Davids 2025, PMID 39705540): voruciclib downregulated MYC and NF-kB gene sets, lowered MCL1 mRNA and reduced Pol II phosphorylation in patients, yet 21 AML patients yielded one morphologic leukaemia-free state and no complete remissions -- achieving the MYC-directed transcriptional effect is feasible and, alone, inactive
resensitises PRC1.1-deficient, MYC-reactivated, menin-resistant cells
collapses short-half-life MYC, the effector of the PRC1.1 bypass
- depends on →BCOR — the other side of the CBX8 conflict, and a target you would be inhibiting in the direction of disease
loss of the PRC1.1 subunit BCOR (or PCGF1) is the initiating lesion
- confers resistance to →Ziftomenib (KO-539, Komzifti) — once-daily menin inhibitor approved in NPM1-mutant AML
epigenetic reactivation of non-canonical menin targets including MYC
- part of →Adaptive, non-genetic resistance — the leukemia keeps the fusion and rewires how it is maintained
the best-characterised named route within the adaptive resistance class