State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
Br J Haematol. 2024 Aug;205(2):568-579. doi: 10.1111/bjh.19591. Epub 2024 Jun 15.
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.
MLL 重排（MLL-r）白血病约占急性髓系白血病（AML）的 10%，预后相对较差，这凸显了新的治疗方案的必要性。MLL 重排产生的 MLL 融合蛋白招募 KDM4C 来介导表观遗传重编程，这是维持 MLL-r 白血病所必需的。在这项研究中，我们使用组合药物筛选来选择性地鉴定 KDM4C 抑制剂 SD70 的协同治疗伙伴。结果表明，SD70 与 MI-503（一种有效的门冬酰胺酶-MLL 抑制剂）的药物组合在不影响正常 CD34 细胞的情况下，协同诱导 MLL::AF9 白血病细胞的凋亡。SD70 和 MI-503 的体内治疗显著延长了 AML 异种移植模型的存活期。SD70 和 MI-503 联合药理学抑制后的 RNA-seq 差异基因表达分析显示，许多基因发生了变化，其中 MYC 靶基因的下调最为显著。总之，这些数据提供了临床前证据，表明 SD70 和 MI-503 的联合应用是治疗 MLL::AF9 AML 的一种有潜力的双重靶向治疗方法。
