AURKB调节MYC癌蛋白稳态促急性T淋巴细胞白血病的功能和机制研究

急性T淋巴细胞白血病(T-ALL)是儿童和青少年中常见的恶性血液肿瘤。目前，临床上主要依赖大剂量化疗诱导缓解，缺乏有效的靶向药物。申请人和同行前期发现，癌蛋白MYC在T-ALL中异常高表达，模式动物上干预MYC能显著抑制T-ALL的发展进程，提示深入探讨MYC的调控机制并据此寻找可行的靶向策略，对T-ALL的靶向治疗具有重要指导意义。通过蛋白组学筛选分析，申请人发现蛋白激酶AURKB和癌蛋白MYC专一结合，维持MYC在T-ALL细胞中的蛋白稳态。本项目拟采用体外细胞模型、模式动物和患者原代样本等研究体系，进一步 1) 探究AURKB调控MYC蛋白稳态的分子机制；2) 检测AURKB-MYC轴在T-ALL发生发展中的作用；3) 模式动物上评估AURKB小分子抑制剂单用或联合用药的疗效。本项目的顺利实施有望揭示MYC信号网络调控T-ALL恶性进展的分子新机制，为T-ALL的靶向治疗提供新思路。

Acute T-cell lymphoblastic leukemia (T-ALL) is a common aggressive and life-threatening hematological malignancy often occurring in children and adolescents, molecular pathogenesis of which remains fully understood. Current clinical intervention of T-ALL involves intensified chemotherapeutics which cause unavoidable side effects and toxicities severely detrimental to young patients. We and others have shown that oncoprotein MYC is essential in T cell leukemogenesis, providing MYC as a therapeutic vulnerability. Due to undruggbale structure of MYC protein, we consider the strategy of indirect targeting of MYC for the inhibition of T cell leukemogenesis. We previously performed a proteomics analysis revealing AURKB as a novel MYC binding partner, which plays a crucial role in regulating MYC protein accumulation. Using combinatory approaches of molecular and cellular assays, animal modeling and primary T-ALL sample analysis, we attempt to further investigate whether and how AURKB-MYC axis functions to put forward T-ALL. To this end, we aim to (1) examine the molecular mechanism whereby AURKB regulates MYC protein stability; (2) study how AURKB-MYC axis promotes T cell leukemogenesis; (3) evaluate the antileukemic effect of AURKB-targeted single or combination therapy. Our work will decipher a previously unsuspected mechanism involved in T-ALL pathogenesis. Ultimately, it raises a possibility and paves a new avenue of translating anti-AURKB therapy in T-ALL treatments.