西达本胺抑制HOXA9/FLT3信号轴协同Venetoclax靶向杀伤FLT3突变型急性髓系白血病及分子机制研究

FLT3-ITD突变是目前急性髓系白血病（AML）治疗的难点，但尚无高效低毒的FLT3靶向药物出现。我们已报道我国自主研发的组蛋白去乙酰化酶抑制剂西达本胺可增敏Bcl-2抑制剂Venetoclax的抗AML效应，后续研究发现其对FLT3突变型AML效果更显著，进一步运用多学科综合研究手段推测西达本胺可能是通过乙酰化修饰抑制HOXA9/FLT3信号轴协同Venetoclax靶向杀伤FLT3突变型AML。基于此，本项目拟开展：①构建FLT3-ITD敲入模型进一步明确西达本胺联合Venetoclax的抗FLT3突变型AML效应；②信号通路干预、启动子结合活性研究阐明两药联合杀伤FLT3突变型AML的分子机制；③人源化小鼠模型进一步验证其治疗潜能和机制；④通过临床样本明确HOXA9水平和FLT3突变载量与杀伤作用的相关性。本项目将为FLT3突变型AML患者的临床治疗提供新策略和科学依据。

FLT3-ITD mutation is a current difficulty in the treatment of acute myeloid leukemia (AML), but there is no high-efficiency and low-toxicity FLT3 targeted agent. We have previously reported that Chidamide, a histone deacetylase inhibitor self-developed by China, could enhance the anti-AML effect of Venetoclax. Follow-up studies have found that combined treatment of Chidamide with Venetoclax exerts a more significant effect on FLT3 mutant AML cells compared to the counterpart. Next, we speculate that the targeted killing activity on FLT3 mutant AML displayed by Chidamide/Venetoclax is a result of inhibition of HOXA9/FLT3 signal axis using multidisciplinary comprehensive study. Based on this, we will 1). further clarify the anti-FLT3 AML effect of Chidamide combined with Venetoclax by construction of FLT3-ITD knock-in cell model; 2). elucidate the molecular mechanisms underlying Chidamide/Venetoclax on FLT3 mutant AML by signal pathway intervention and promoter binding activity of target genes; 3). determine the therapeutic efficacy and mechanisms of Chidamide/Venetoclax in humanized mouse models, as well as 4). illustrate the correlation between HOXA9 expression/FLT3 mutation load and the cytotoxicity exerted by the combined treatment. This project will uncover the therapeutic potential and mechanism of combining Chidamide with Venetoclax, which offered a new therapeutic strategy for the clinical treatment of FLT3 mutant AML patients with poor prognosis.