A phosphosite on a menin target predicts who responds to a menin inhibitor
also called MEF2C S222 · p-MEF2C biomarker · ziftomenib sensitivity marker
MEF2C is a protein switched on by the KMT2A-menin machinery. Phosphorylating it at one spot marks the leukaemias that respond to menin-blocking drugs, and adding a drug that stops that phosphorylation makes the menin drug work better.
The same thing, for a scientist
Phosphoproteomics across 14 primary T-ALL samples and 8 cell lines identified **MEF2C S222 phosphorylation, mediated by CDK1/2 and ERK1/2, as a predictor of ziftomenib sensitivity**. MEF2C overexpression promoted proliferation and ziftomenib resistance; knockdown impaired growth. **Ziftomenib synergised with CDK1/2 and ERK1/2 inhibitors in vitro and improved survival in xenografts.** MEF2C is a canonical menin-KMT2A target, so this is a phosphosite on a **downstream effector** rather than a contact on the fusion - but it is the only entry in this beat where a phosphorylation state has been shown to predict response to the drug class this graph is built around, and it is the only one with a matched combination result. The disease is T-ALL, including HOXA-low cases, not KMT2A-rearranged leukaemia, and that limit must travel with the finding.
What the study did
Ziftomenib, revumenib and VTP50469 were tested across 14 primary T-ALL samples and 8 cell lines spanning HOXA-high and HOXA-low genotypes, with transcriptomics, proteomics and phosphoproteomics. Menin inhibitors suppressed growth in a subset of both genotypes; ziftomenib reduced xenograft tumour burden without major toxicity. On treatment, HOXA, MEIS1 and MEF2C fell and T-cell differentiation programmes rose.
The phosphoproteomic result: p-MEF2C S222, written by CDK1/2 and ERK1/2, marks the sensitive subset. MEF2C overexpression conferred resistance; knockdown impaired growth. Ziftomenib plus a CDK1/2 or ERK1/2 inhibitor synergised in vitro and extended survival in xenografts 1.
How far it transfers to KMT2A-rearranged disease
Not established, and the beat should not pretend otherwise. The study is T-ALL. MEF2C is a shared node - it is a menin-KMT2A target in both diseases and this graph already treats it as part of the fusion's programme - and the same menin inhibitors are the drugs in question. That makes the transfer plausible and untested.
What makes it worth writing down for a KMT2A beat is the shape of the result: a phosphorylation state on a downstream effector, not on the fusion, predicting response to a fusion-directed drug. If the same holds in KMT2A-rearranged AML, then a phospho-western would stratify patients for menin inhibition, and a CDK or ERK inhibitor would be a rational partner. Neither has been tried in KMT2A-rearranged disease.
The standing caution applies with force: an absence of testing is not a negative result. Nobody has looked for p-MEF2C S222 as a menin-inhibitor biomarker in KMT2A-rearranged leukaemia.
| substrate | MEF2C |
|---|---|
| site | S222 |
| consequence | predicts sensitivity to the menin inhibitor ziftomenib; MEF2C overexpression confers resistance |
| disease studied | T-lineage acute lymphoblastic leukaemia (HOXA-high and HOXA-low) |
| tested in kmt2a rearranged | false |
| cohort | 14 primary T-ALL samples, 8 cell lines, xenografts |
| combination | ziftomenib + CDK1/2 inhibitor or ERK1/2 inhibitor, synergistic in vitro and in xenografts |
kinases
[ "CDK1", "CDK2", "ERK1", "ERK2" ]
- Adding a CDK1/2 inhibitor to a menin inhibitor stacks myelosuppression on a marrow already failing, in patients who are frequently infants. Preclinical synergy says nothing about that.
- A resistance mechanism is already written into the finding: MEF2C overexpression confers ziftomenib resistance. Selecting patients by p-MEF2C selects for a pathway whose upregulation is the escape route.
- If S222 phosphorylation is a response predictor because it marks a proliferative state rather than a menin dependency, the biomarker will fail in the slower-growing disease where it would be most useful.
- The finding is in T-ALL. Importing it into KMT2A-rearranged leukaemia without testing is exactly the partner-imported-evidence failure this graph already has a hypothesis entry about.
- Is p-MEF2C S222 present in KMT2A-rearranged AML and B-ALL, and does it track menin-inhibitor response there? A phospho-western on banked samples would answer it.
- Does menin inhibition itself change S222 occupancy, which would make it a pharmacodynamic marker rather than a predictive one? Those are different clinical uses.
- Is the CDK1/2 synergy a MEF2C effect or a general cell-cycle effect? The abstract does not separate them.
- How does this relate to the CDK1 activity signature that separates the two KMT2A-rearranged AML phosphoproteomic groups? Both point at CDK1 in menin-axis leukaemia and neither cites the other.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Phosphoproteomic profiling identified MEF2C S222 phosphorylation, mediated by CDK1/2 and ERK1/2, as a predictor of ziftomenib sensitivity in T-lineage ALL; MEF2C overexpression promoted proliferation and ziftomenib resistance while knockdown impaired growth, and ziftomenib synergised with CDK1/2 and ERK1/2 inhibitors in vitro and improved survival in xenografted mice.
Targeting Menin in T-lineage Acute Lymphoblastic Leukemia. · Shimamoto K, et al. · Mol Cancer Ther 2026What this evidence cannot show
Abstract read 2026-09-19; full text not retrieved. The cohort is 14 primary T-ALL samples and 8 cell lines - small for a predictive biomarker claim, with no independent validation cohort described in the abstract. The disease is T-ALL, not KMT2A-rearranged leukaemia. 'Mediated by CDK1/2 and ERK1/2' is an inference from inhibitor experiments plus kinase-substrate prediction unless the full text shows direct assays. A 2026 publication with no replication.
Evidence that argues against this (2)
- A biomarker derived and tested in the same small sample set is the classic setting for optimism; this graph's own standing caution about selectivity claims requires splitting the index arm and reporting both halves before a stratification claim is believed, and a 14-sample cohort cannot support that split. Casado P et al. 2023
- Combining a menin inhibitor with a CDK1/2 inhibitor adds two agents with overlapping myelosuppression in a population already defined by marrow failure, and menin inhibitors carry differentiation syndrome and QTc liabilities. Synergy in a xenograft is not a tolerable combination in a child. Shimamoto K et al. 2026
p-MEF2C S222 predicts sensitivity in T-ALL; untested in KMT2A-rearranged disease
a phosphosite on a menin-KMT2A target that gates response to menin inhibition
downstream-effector phosphosite in the enumeration