泛素-蛋白酶体途径介导的p53蛋白降解致FLT3-ITD急性髓系白血病耐药研究

FLT3-ITD是急性髓系白血病（AML）中最常见基因突变之一，导致AML预后不良。目前FLT3的靶向抑制剂（FLT3i）临床疗效并不理想，而FLT3i耐药机制仍未明确。我们前期研究首次发现抑制FLT3可引起FLT3-ITD AML细胞中p53蛋白泛素化水平升高，并发生降解，导致细胞对FLT3i耐药。我们推测泛素-蛋白酶体系统介导的p53蛋白降解是FLT3i耐药的重要机制。本课题研究以下科学问题：①FLT3i引起p53经泛素-蛋白酶体途径降解的分子机制；②p53蛋白降解是导致细胞对FLT3i耐药的原因；③利用蛋白酶体抑制剂阻断p53降解，能否促进FLT3i杀伤FLT3-ITD AML。本课题将阐明经泛素-蛋白酶体途径介导的p53蛋白降解在FLT3-ITD AML的耐药及疾病进展中的作用和意义，建立FLT3i和蛋白酶体抑制剂联合治疗FLT3-ITD AML的方案，为临床治疗提供新策略。

FLT3-ITD mutation is one of the most frequent mutations in AML, which confers a poor prognosis for AML. There are a number of targeted inhibitors on FLT3, but clinical studies have shown that the efficacy of these inhibitors is not good，and the mechanisms resulting in FLT3 inhibitor resistance remain unclear. Our preliminary study found that inhibition of FLT3 promoted ubiquitination of p53 and induced p53 protein degradation in FLT3-ITD AML, leading to FLT3 inhibitor resistance. We propose that p53 protein degradation plays a crucial mechanism in resisting the anti-leukemia effect of FLT3 inhibitors. Therefore, this project will study the following scientific issues from three levels (molecular, cellular and animal models): (1) The molecular mechanism of FLT3 inhibitors in inducing p53 degradation through ubiquitin-proteasome system; (2) Whether p53 degradation would result in FLT3 inhibitor resistance; (3) Whether blocking p53 degradation by proteasome inhibitor would promote FLT3 inhibitors to eliminate FLT3-ITD AML. This topic will reveal the role and significance of proteasome mediated p53 degradation in FLT3-ITD AML drug resistance and leukemia progression, therefore, providing a new strategy for clinical treatment of FLT3-ITD AML, and laying a research foundation for the FLT3 inhibitors and proteasome inhibitors combination protocol.