DOI RECORD
Pharmacological inhibition of PRKDC-mediated DNA damage response by 3-hydroxyflavone selectively alleviates MLL-rearranged acute myeloid leukemia
Abstract
Abstract Rearrangements of the mixed lineage leukemia (MLL) gene in acute myeloid leukemia (AML) have been associated with resistance to chemotherapy, and there is currently an unmet clinical need for effective targeted therapies. In this study, we performed high-throughput drug screening and identified 3-hydroxyflavone (3-HF) as a selective inhibitor of the survival and growth of MLL-rearranged (MLL-r) AML cells, while exhibiting minimal effects on leukemia cells with wild-type MLL. Mechanistically, 3-HF suppresses the transcription of MLL-targeted genes and exerts anti-leukemic activity by disrupting PRKDC -mediated DNA damage repair. Additionally, 3-HF enhances chemosensitivity in MLL-r AML cells and demonstrates synergistic anti-leukemic effects when combined with cytarabine, a standard chemotherapy agent, both in vitro and in vivo using two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukemia. Our findings provide a novel therapeutic strategy targeting PRKDC -mediated DNA damage repair for MLL-r leukemia.