Targeting menin in T-lineage acute lymphoblastic leukemia.

Area of Science:

• Hematology and Oncology
• Molecular Biology
• Pharmacology

Background:

• T-lineage acute lymphoblastic leukemia (T-ALL), especially HOXA-high subtypes, presents significant therapeutic challenges with poor outcomes in relapsed/refractory disease.
• While menin inhibitors are approved for KMT2A-rearranged leukemias, their efficacy and predictive biomarkers in T-ALL remain undefined.
• This research addresses the urgent need for targeted therapies in T-ALL by investigating menin inhibition.

Purpose of the Study:

• To evaluate the therapeutic efficacy of menin inhibitors in T-ALL.
• To identify molecular biomarkers that predict sensitivity to menin inhibition in T-ALL.
• To explore combination strategies for enhanced T-ALL treatment.

Main Methods:

• Tested menin inhibitors (ziftomenib, revumenib, VTP-50469) on 14 primary T-ALL samples and 8 cell lines with varying HOXA genotypes.
• Utilized in vitro sensitivity assays, xenograft mouse models, transcriptomics, proteomics, and phosphoproteomics to analyze drug response.
• Conducted MEF2C modulation experiments and combination studies with CDK1/2 and ERK1/2 inhibitors.

Main Results:

• Menin inhibitors demonstrated efficacy in a subset of HOXA-high and HOXA-low T-ALL samples and reduced tumor burden in xenografts.
• Treatment led to downregulation of menin targets (HOXA, MEIS1, MEF2C) and activation of T-cell differentiation programs.
• MEF2C S222 phosphorylation, mediated by CDK1/2 and ERK1/2, was identified as a key predictor of ziftomenib sensitivity; MEF2C overexpression conferred resistance.

Conclusions:

• A subset of T-ALL, characterized by high MEF2C S222 phosphorylation, is sensitive to menin inhibition.
• Combination therapy with ziftomenib and CDK or ERK inhibitors shows synergistic efficacy in vitro and in vivo.
• These findings support biomarker-driven clinical trials for menin inhibition in relapsed/refractory T-ALL.