Pharmacological inhibition of PRKDC-mediated DNA damage response by 3-hydroxyflavone selectively alleviates MLL-rearranged acute myeloid leukemia

Genetic rearrangements involving mixed lineage leukemia (MLL-r) in acute myeloid leukemia (AML) have been associated with resistance to chemotherapy, and there is currently a clinical unmet 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-r AML cells, while having minimal effects on leukemia cells with wildtype MLL. Mechanistically, 3-HF suppresses the transcription of MLL-targeted genes and exerts antileukemic activity by disrupting PRKDC-mediated DNA damage repair. Additionally, 3-HF enhances chemosensitivity in MLL-r AML cells and demonstrates synergistic antileukemic 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 strategy and targeted therapeutic drug disrupting PRKDC-mediated DNA damage repair pathways for MLL-r leukemia.