Notch-Myc通路在T细胞型急性淋巴细胞白血病PI3K/mTOR双重抑制剂耐药中的作用及机制研究

T细胞型急性淋巴细胞白血病（T-ALL）为高度侵袭性血液系统恶性疾病。PI3K/mTOR双重抑制剂作为靶向药物治疗T-ALL近年来受到广泛关注，但耐药问题限制了该药物疗效。研究表明，Notch信号通路异常活化与T-ALL化疗抵抗密切相关。本课题前期实验结果发现在T-ALL中应用PI3K/mTOR抑制剂可促进细胞凋亡，但同时激活Notch及其下游Myc。因此我们设想：Notch-Myc异常活化可能是导致PI3K/mTOR抑制剂耐药的重要原因。本项目拟通过应用T-ALL细胞株、T-ALL干细胞以及小鼠T-ALL肿瘤模型，从分子、细胞、组织以及动物整体水平等多层次探讨Notch-Myc信号通路在PI3K/mTOR双重抑制剂耐药中的作用。本课题为逆转PI3K/mTOR抑制剂获得性耐药提供新的方法和思路。

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive form of hematological malignancy. In recent years, PI3K/mTOR inhibitors are widely used for the treatment of T-ALL. However, the development of acquired resistance limits the efficacy of these drugs. Dysregultion of Notch signaling pathway plays a crucial role in acquired drug resistance of T-ALL. In our previous study, we observed that PI3K/mTOR inhibitors could induce apoptosis in T-ALL cells, but simultaneously activate Notch-Myc signaling. Thus, we hypothesized that aberrant activation of Notch-Myc signaling might be an important cause of acquired resistance to PI3K/ mTOR inhibitors. Using T-ALL cell lines, leukemic stem cells and T-ALL xenograft models, we planned to investigate the role of Notch-Myc signaling on the acquisition of resistance to dual PI3K/mTOR inhibitors. This project might pave the way for a better understanding of acquired resistance to dual PI3K/mTOR inhibitors and provide new strategies for the reversal of drug resistance in T-ALL.