Combination of SD70 and MI-503 exerts a synergistic effect against MLL:: AF9-driven AML

Acute myeloid leukemia (AML), a heterogeneous hematologic malignancy, is the most common form of acute leukemia in adults. MLL rearrangements (MLL-r) are observed in approximately 10% of AML and are associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusions recruit KDM4C to mediate epigenetic reprogramming, which is required for maintenance of MLL-r leukemia. 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-r leukemia cells without affecting normal CD34+ cells. In vivo treatment with SD70 and MI-503 significantly prolongs 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-target therapy for MLL-r AML. Overall design: To investigate the molecular mechanism underlying the synergistic effect of SD70 and MI-503, we performed RNA-seq analysis on MOLM13 cells treated with DMSO, single agent alone, or the combination.

急性髓系白血病（Acute myeloid leukemia, AML）是一种异质性血液系统恶性肿瘤，也是成人最常见的急性白血病类型。MLL重排（MLL rearrangements, MLL-r）在约10%的AML病例中被检出，且与相对较差的预后相关，这凸显了开发新型治疗方案的必要性。MLL融合蛋白会招募KDM4C以介导表观遗传重编程，该过程是维持MLL-r白血病所必需的。本研究采用组合药物筛选策略，选择性筛选KDM4C抑制剂SD70的协同治疗搭档。结果显示，SD70与强效Menin-MLL抑制剂（Menin-MLL inhibitor）MI-503联合给药，可在不影响正常CD34+细胞的前提下，协同诱导MLL-r白血病细胞发生凋亡。体内实验表明，SD70与MI-503联合治疗可显著延长AML异种移植模型小鼠的生存期。通过RNA测序（RNA-seq）对SD70和MI-503联合药理抑制后的样本进行差异基因表达分析，发现大量基因表达发生改变，其中MYC靶基因的下调最为显著。综上，本研究数据为SD70与MI-503联合疗法作为MLL-r AML的潜在双靶点治疗方案提供了临床前证据。整体实验设计：为探究SD70与MI-503协同作用的分子机制，我们对经二甲基亚砜（DMSO）、单一药物或联合药物处理的MOLM13细胞进行了RNA测序分析。