Synergistic effects of the KDM4C inhibitor SD70 and the menin inhibitor MI ‐503 against MLL::AF9 ‐driven acute myeloid leukaemia

作者：Wenqi Zhu, Yiyi Ding, Wanling Huang, Nini Guo, Qian Ren, Nan Wang, Xiaotong Ma · 发表于：British Journal of Haematology · 年份：2024 · DOI：10.1111/bjh.19591 · 被引用次数：10 · 研究领域：Protein Degradation and Inhibitors、Multiple Myeloma Research and Treatments、Histone Deacetylase Inhibitors Research

Summary MLL ‐rearranged ( MLL ‐r) leukaemia is observed in approximately 10% of acute myeloid leukaemia (AML) and is associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusion proteins produced by MLL rearrangements recruit KDM4C to mediate epigenetic reprogramming, which is required for the maintenance of MLL ‐r leukaemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI‐503, a potent menin‐MLL inhibitor, induced synergistically enhanced apoptosis in MLL::AF9 leukaemia cells without affecting normal CD34 + cells. In vivo treatment with SD70 and MI‐503 significantly prolonged survival in AML xenograft models. Differential gene expression analysis by RNA‐seq following combined pharmacological inhibition of SD70 and MI‐503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI‐503 is a potential dual‐targeted therapy for MLL::AF9 AML.