抑癌基因PTEN在慢性淋巴细胞白血病中异常表达机制及与利妥昔单抗耐药机制研究

PTEN是PI3K/Akt通路重要拮抗因子，其在慢性淋巴细胞白血病（CLL）中异常表达机制及与利妥昔单抗耐药机制尚不完全清楚。我们前期研究结果提示：CLL患者PTEN低表达，并与预后和利妥昔单抗耐药相关；PTEN基因存在高甲基化；miRNA可调控PTEN表达。为此，我们提出假说：CLL中PTEN低表达可能由于PTEN基因突变或缺失所致；表观遗传学可调控PTEN表达；PTEN/PI3K/Akt异常与利妥昔单抗耐药相关。为验证此假说，本课题拟研究CLL患者PTEN基因突变、缺失情况；阐明PTEN/PI3K/Akt信号通路在CLL细胞增殖和凋亡中的作用；揭示表观遗传学（甲基化、miRNA）对PTEN表达的调控机制；探讨PTEN/PI3K/Akt异常与利妥昔单抗耐药关系。通过研究阐明PTEN异常在CLL发病机制和利妥昔单抗耐药机制中作用，为开展相应靶向治疗，预测和克服利妥昔单抗耐药提供理论依据。

The tumor suppressor gene PTEN is a crucial antagonistic factor of PI3K/Akt pathway. The mechanism of abnormal PTEN expression and its role in rituximab resistance in chronic lymphocytic leukemia (CLL) are not clear. Our previous findings: compared to controls, patients with CLL presented a lower expression level of PTEN and its expression was associated with prognosis of CLL and resistance of rituximab; hypermethylation of PTEN gene CpG island was found in CLL cells; miRNA regulated PTEN expression. We propose the hypothesis: PTEN gene abnormalities result in low expression of PTEN in CLL; epigenetic regulation of PTEN expression is shown in CLL; The abnormal activation of PTEN/PI3K/Akt is associated with rituximab-resistant.This project intends to investigate: PTEN gene abnormalities (including mutation and deletion) in CLL; PTEN/PI3K/Akt signaling pathway in CLL cell proliferation and apoptosis at vitro cellular level; epigenetic regulation mechanisms (methylation and miRNA) of PTEN expression; the relation between abnormal PTEN/PI3K/Akt pathway and rituximab resistance in CLL cells. Through research, the roles of the PTEN gene in pathogenesis of CLL and rituximab resistanc will be understood deeply, and a theoretical basis of related target therapy as well as predicting and overcoming rituximab-resistant will be provided.