BAG3在慢性淋巴细胞白血病凋亡及迁移中的作用机制研究

Chronic lymphocytic leukemia (CLL) is a type of clonal B lymphocytic proliferative disease. BAG3 (Bcl-2-associated athanogene 3),as a member of BAG family, is shown to sustain cell survival and underlies resistance to chemotherapy in many human neoplastic cells. However, the roles of BAG3 in CLL remain unknown. Our preliminary data found that the expression level of BAG3 in CLL cells was significantly higher than normal B cells, which was associated with some known prognostic factors such as IgHV. Futhermore, we showed that BAG3 can inhibit the apoptosis of CLL cells and enhance their migiration ablity. These results imply that abberant expression of BAG3 plays important roles in CLL. Here, we propose 4 further works to investigate the role of BAG3 in CLL: 1)to check the expression of BAG3 and its clinical significance in larger CLL samples; 2) to study how BAG3 inhibits the apoptosis of CLL cells; 3) to explore how BAG3 enhances CLL cell migration; 4) to investigate the effect of BAG3 on the CLL tumor-bearing mice in vivo. This project will deeply identify the molecular mechanisms of BAG3 in the pathogenesis and progression of CLL, which may provide a promising theraputic target in CLL.

慢性淋巴细胞白血病(CLL) 是一种B 淋巴细胞克隆增殖性疾病，BAG3(Bcl-2-associated athanogene 3)属于BAG 家族蛋白，通过抑制细胞凋亡而促进肿瘤细胞产生化疗抵抗。然而，BAG3 在CLL 中的作用机制仍未阐明。我们的前期研究证实BAG3在CLL 中表达升高，并与IgHV 等已知预后因素相关；体外实验初步证实下调BAG3 表达能促进CLL 细胞凋亡及抑制CLL 细胞迁移。本项目拟进一步开展如下工作：1)大样本研究CLL 患者中BAG3 表达及其临床意义；2)深入探讨BAG3 抑制CLL 细胞凋亡的作用机制；3)深入研究BAG3 在CLL 迁移中的作用机制；4)研究修饰BAG3 表达对CLL 小鼠体内致瘤性的作用。本项目将深刻揭示BAG3 在CLL 发病中的分子机制，提供该病的一个治疗新靶标，具有重要的理论意义及潜在的临床应用价值。

BAG3(Bcl-2-associated athanogene 3)属于BAG 家族蛋白，通过抑制细胞凋亡而促进肿瘤细胞产生化疗抵抗，而起在血液肿瘤中的具体作用机制阐述不明。通过研究我们发现在慢性淋巴细胞白血病(CLL)中：（1）BAG3在慢性淋巴细胞白血病中表达升高，并可能与某些已知预后因素、临床特征及化疗耐药相关；（2）BAG3 表达水平在某些亚群CLL患者中与患者生存相关;（3） BAG3在CLL细胞中可能通过影响抗凋亡蛋白表达水平在CLL中起抑制凋亡作用;（4）BAG3与抗凋亡蛋白Mcl-1协同作用导致CLL凋亡受抑，该机制可能为ABT-199耐药作用机制之一;（5） BAG3可通过调节CLL细胞表面CXCR4-CXCL12表达水平影响CLL细胞迁移能力。BAG3为CLL治疗的潜在治疗靶标。（6）BAG3水平表达与急性髓系白血病（AML）的一些公认预后因子无相关性，其生存无影响，BAG3不是AML的预后因子。