Akt2/PKM2轴介导的糖代谢异常参与PTEN缺失的急性T淋巴细胞白血病激素耐药的机制研究

糖皮质激素耐药是急性淋巴细胞白血病（ALL）复发的主要原因，与T-ALL常发生的PTEN缺失和突变密切相关。糖代谢异常在肿瘤的发生发展中起着关键作用而成为研究热点，但在ALL激素耐药中的分子机制仍未阐明。我们预实验发现PTEN缺失型T-ALL细胞对激素高度耐药并伴随细胞内有氧糖酵解水平升高，结合前期研究发现PTEN下游的Akt2是激素耐药的关键靶点，由此提出假说PTEN/Akt2轴调控糖酵解关键酶PKM2介导糖代谢异常参与激素耐药。本课题在前期工作基础上拟揭示PTEN基因多态性在T-ALL激素耐药中的作用及临床意义；明确Akt2对PKM2的上游调控机制，阐明Akt2-PKM2为核心的糖代谢调控网络；建立T-ALL小鼠荷瘤模型验证靶向Akt2/PKM2轴在体内的抗激素耐药效应。本课题对于揭示糖代谢异常参与T-ALL激素耐药的分子机制具有重要的理论价值，可为针对糖代谢异常的靶向治疗提供基础。

Glucocorticoid resistance is the leading cause of the relapse of acute lymphoblastic leukemia (ALL), which is closely related to the deletion and mutation of PTEN gene that often occur in T-ALL. Abnormal glycometabolism plays a key role in the aggression of malignancies and has become a hotspot, but its role in the molecular mechanism of glucocorticoid resistance has not been clarified. Our preliminary experiment found that PTEN-null T-ALL cells were highly resistant to glucocorticoid accompanied by increased intracellular aerobic glycolysis. Combined with the finding of our previous study that Akt2, the downstream of PTEN , was the key target of glucocorticoid resistance in ALL; it was hypothesized that the PTEN/Akt2 axis regulates the key enzyme of glycolysis, PKM2, to mediate abnormal glycometabolism and leads to glucocorticoid resistance. Based on the previous work, this study intends to reveal the role of PTEN gene polymorphism in T-ALL glucocorticoid resistance and its clinical significance; to clarify the mechanism of Akt2 regulating PKM2; to explore the regulation network of glycometabolism mediated by Akt2/PKM2 axis; and to establish T-ALL xenograft mouse model to verify the anti-glucocorticoid resistance effect of targeting Akt2/PKM2 axis in vivo. This study aims to clarify the molecular mechanism of abnormal glycometabolism in T-ALL glucocorticoid resistance and possible therapeutic targets, which has important basic and clinical significance.