Menin inhibitor DS-1594b drives differentiation and induces synergistic lethality in combination with Venetoclax in acute myeloid leukemia cells with rearranged MLL1 and NPM1 mutations

MLL1 (KMT2A) rearrangements and NPM1 mutations are associated with acute leukemias whose pathogenesis is critically influenced by protein-protein interactions between menin and MLL1. We hypothesized that targeting the menin-MLL interaction using DS-1594b and targeting the antiapoptotic factor BCL-2 using venetoclax (ABT-199) may promote differentiation and enhance lethality in patients with MLL1-rearranged and NPM1-mutated leukemias. We treated acute myeloid leukemia (AML) cell lines with MLL1 rearrangements, NPM1 mutations, and no mutations and samples from patients with primary AML with ABT-199 alone, DS-1594b alone, and their combination. We measured proliferation, viability, apoptosis, and differentiation using several assays, Western blotting, and BH3 profiling. Treatment with DS-1594b and ABT-199 exerted significant synergy, resulting in enhanced differentiation and inhibited proliferation across several cell lines. In the PDX model, DS-1594b single-agent treatment significantly extended survival (pv=***). Compared with DS-1594b monotherapy, the combination of DS-1594b and ABT-199 more profoundly reduced leukemic burden and prolonged mouse survival (pv=***). Overall, we observed synergistic effects on differentiation induction and proliferation inhibition, both in vitro and in vivo. Menin inhibition is the primary driver of transcription changes in this model, and impact on the expression of antiapoptotic regulators provide mechanistic explanation for the synergy observed between these drugs. Together, this underscores the promise of this combination strategy as a novel therapeutic approach for improving treatment outcomes in patients with these specific genetic alterations.