WSTF-RPB1介导的急性髓细胞白血病靶向治疗耐药的分子机制及治疗策略研究

靶向药物治疗急性髓细胞白血病（AML）易发生耐药，其原因错综复杂且机制不明。我们的前期研究发现AML对靶向FLT3的抑制剂治疗耐受的发生过程中，促进DNA损伤修复的转录因子WSTF和RNA聚合酶II大亚基（RPB1）被激活且发生共定位，联合使用RNA聚合酶II（RNAPII）抑制剂雷公藤甲素可增强FLT3抑制剂对AML的治疗效果并逆转耐药。在此基础上，本研究将进一步深入探讨：1）WSTF-RPB1激活是靶向药物治疗AML过程中发生的主要耐药机制之一；2）在细胞模型、皮下异种移植瘤和全身性白血病模型中系统评价并寻找RNAPII抑制剂增强靶向药物抗AML的药物组合方案；3）阐明联合治疗的分子机理并应用靶标确证技术探索雷公藤甲素抗耐药的新靶点。从FLT3抑制剂耐药性着手，通过阐明靶向药物治疗AML耐药发生过程中的关键机理，本研究可为引领和推进新一代抗白血病的药物设计及组合治疗策略提供分子基础。

Drug resistance is more susceptible to develop during the treatment of acute myeloid leukemia (AML) with targeted therapy, but the key reasons for this are complicated and the underlying mechanisms remain elusive. Our previous study found that transcription factor WSTF and RNA polymerase II large subunit (RPB1), which promote DNA damage repair, were activated and co-localized during the development of tolerance to inhibitors targeting FLT3 in AML. Furthermore, the combination of RNA polymerase II (RNAPII) inhibitor triptolide enhanced the anti-AML effect of FLT3 inhibitors and reversed their resistance. Based on these preliminary findings, the study will further explore: 1) activation of WSTF-RPB1 is one of the main mechanisms of resistance to targeted therapy in AML; 2) the combination strategy with RNAPII inhibitors to enhance the anti-AML effect of targeted therapy by evaluating systematically in cell models，subcutaneous xenograft models and systemic leukemia models; 3) the molecular mechanism of combination therapy and the potential new target of triptolide dealing with drug resistance using target confirmation technology. Starting with resistance to FLT3 inhibitors and by clarifying the key events and mechanisms of resistance to targeted therapy, the study is expected to provide molecular basis for leading and promoting a next-generation drug design as well as combination strategies in leukemia.