Targeting Menin in T-Lineage Acute Lymphoblastic Leukemia [MEF2CKD]

Sensitivity was not correlated with HOXA expression or KMT2A rearrangements, and in vivo treatment significantly reduced tumor burden in xenograft models without notable toxicity. Transcriptomic and proteomic analyses confirmed on-target activity, including downregulation of menin targets and activation of differentiation pathways.

Phosphoproteomic profiling identified phospho-MEF2C (S222) as a key marker of sensitivity, regulated by CDK and MAPK signaling. Combination treatment with ziftomenib and CDK1/2 or ERK1/2 inhibitors showed synergistic effects, suggesting a mechanistic link between menin inhibition and p-MEF2C–driven T-ALL vulnerability.