Work

Menin inhibitor DS-1594b drives differentiation and induces synergistic lethality in combination with venetoclax in acute myeloid leukemia cells with rearranged mixedlineage Leukemia and mutated nucleophosmin-1

Year: 2025

Type: article

Abstract: Mixed-lineage leukemia (MLL) rearrangements (MLLr) and nucleophosmin-1 (NPM1) mutations are associated with acute leukemias whose pathogenesis is critically influenced by protein-protein interactions between menin and MLL. We hypothesized that targeting the menin-MLL interaction using DS-1594b and blocking the anti-apoptotic BCL-2 protein using venetoclax may promote differentiation and enhance eradication of MLLr and NPM1-mutated leukemias models. We treated acute myeloid leukemia (AML) cell lines with MLLr, NPM1 mutations, other leukemias and primary samples from AML patients with venetoclax alone, DS-1594b alone, and their combination. We measured proliferation, viability, apoptosis, and differentiation using a variety of cellular assays, western blotting, and BH3 profiling. Treatment with DS-1594b and venetoclax exerted significant synergy, resulting in enhanced differentiation and inhibited proliferation across several cell lines. In the NPM1-mutated AML patient-derived xenograft model, DS-1594b single-agent treatment significantly extended survival. Importantly, compared with DS-1594b monotherapy, the combination of DS-1594b and venetoclax more profoundly reduced leukemic burden and prolonged mouse survival. Menin inhibition was the primary driver of transcription changes in this model and impacted the expression of anti-apoptotic regulators, providing a mechanistic explanation for the synergy observed between these drugs. Overall, we observed synergistic effects on differentiation induction and proliferation inhibition, both in vitro and in vivo. Together, our studies underscore the promise of this combination strategy as a novel therapeutic approach for improving treatment outcomes in patients with these specific genomic alterations.

Source: Haematologica

DOI: 10.3324/haematol.2024.286833