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

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.