Abstract 7069: Co-targeting menin and LSD1 dismantles oncogenic programs and restores differentiation in MLL-rearranged acute myeloid leukemia.

Abstract Acute myeloid leukemia (AML) with KMT2A-rearrangement carries a poor prognosis, underscoring the urgent need for new therapeutic approaches. Menin inhibitors demonstrate promising anti-leukemic activity in KMT2A-r AML; however, their efficacy as monotherapy may be limited by partial responses and emerging resistance mutations. Combination strategies using epigenetic modulators may enhance their therapeutic potential. In this study, we performed a combination drug screen using an epigenetic compound library in KMT2A-r AML cells to identify synergistic agents that could potentiate menin inhibitor activity. MV4-11 cells were treated with DSP-5336 (menin inhibitor) to optimize assay performance (Z′ 0.5). Cells were then screened with a 932-compound epigenetic library to assess drug effects alone or with DSP-5336. Follow-up studies used ORY-1001 (LSD1 inhibitor) and SNDX-5613 (menin inhibitor) across dose ranges. Viability, IC50, and synergy were evaluated using SynergyFinder 2.0. Mechanistic analyses included Western blotting, co-IP, ChIP-qPCR, CUT Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7069.