Abstract 5407: Identifying synthetic lethality targets in DDX41-mutated MDS/AML

DDX41 (DEAD-box helicase 41) is a member of the DEAD-box helicase family, critical for RNA metabolism and genome stability. Mutations in DDX41 are strongly associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly in patients carrying inherited mutations or somatic alterations. Among these, the R525H missense mutation in DDX41 is found in over 70% of affected individuals, impairing helicase activity and contributing to disease pathology. Directly targeting mutant DDX41 (e.g., R525H) with inhibitors remains challenging due to the structural similarity of mutant and wild-type (WT) proteins, as well as the conserved helicase domains shared by the 37 DEAD-box helicases in humans. To overcome these challenges, we are leveraging synthetic lethality (SL) as an innovative therapeutic strategy. Bioinformatic analyses identified potential SL partners of DDX41, including WRN and DDX23. Functional validation experiments revealed that inhibiting WRN helicase selectively impairs the growth of DDX41-deficient cells. In DDX41-knockout HeLa cells, treatment with WRN inhibitors NSC 617145 and HRO761 significantly reduced cell growth compared to WT controls. Similarly, in DDX41-knockdown U2OS cells, WRN inhibitors markedly inhibited cell proliferation compared to WT cells. Future studies aim to elucidate the molecular mechanisms underlying SL interactions between DDX41 and its partners, providing insights into the therapeutic potential of targeting these vulnerabilities. This work offers a promising avenue for developing novel treatments for MDS/AML patients harboring DDX41 mutations, ultimately improving clinical outcomes. Citation Format: Sohaumn Mondal, Shizuo Yang, Vincent Maranda, Frederick Vizeacoumar, Franco Vizeacoumar, Yuliang Wu. Identifying synthetic lethality targets in DDX41-mutated MDS/AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5407.