Targeting menin in T-lineage acute lymphoblastic leukemia - PubMed
4 hours ago
- #menin inhibitors
- #targeted therapy
- #T-ALL
- T-lineage acute lymphoblastic leukemia (T-ALL) lacks effective targeted therapies, especially for relapsed/refractory cases.
- HOXA-high T-ALL is aggressive and often resistant to standard treatments.
- Menin inhibitors, approved for KMT2A-rearranged leukemias, show potential efficacy in T-ALL but lack defined biomarkers.
- Study evaluates menin inhibitors (ziftomenib, revumenib, VTP-50469) in 14 primary T-ALL samples and 8 cell lines.
- Menin inhibitors suppressed leukemic growth in both HOXA-high and HOXA-low T-ALL samples.
- Ziftomenib reduced tumor burden in xenografts without major toxicity.
- Treatment down-regulated menin targets (HOXA, MEIS1, MEF2C) and upregulated T-cell differentiation programs.
- Phosphoproteomic studies identified MEF2C S222 phosphorylation as a predictor of ziftomenib sensitivity.
- MEF2C overexpression promoted proliferation and resistance, while knockdown impaired growth.
- Ziftomenib synergized with CDK1/2 and ERK1/2 inhibitors, improving survival in xenografted mice.
- High p-MEF2C S222 defines a T-ALL subset sensitive to menin inhibition.
- Combination therapy with CDK or ERK inhibitors shows synergistic efficacy, supporting clinical trials.