γH2AX组成性表达弥漫大B细胞淋巴瘤的发病和耐药机制研究

弥漫大B细胞淋巴瘤具有复杂的基因组异常，与免疫化疗预后密切相关，DNA损伤修复异常是其发生的重要原因。γH2AX是DNA双链断裂可靠的分子标记。我们前期研究发现约半数初诊患者表达γH2AX，是免疫化疗独立不良预后因素；基因芯片研究揭示这类患者具有独特的基因表达谱，DNA双链断裂a-NHEJ修复基因高表达；体外研究证实γH2AX表达与阿霉素耐药相关，PARP1抑制剂能够克服耐药。因此，我们推测γH2AX组成性表达弥漫大B细胞淋巴瘤是该疾病重要的亚型，a-NHEJ修复选择性激活是其发病和耐药的重要机制。本项目以肿瘤组织、细胞系和小鼠模型为研究对象，应用分子生物学和蛋白质组学的方法系统研究诱导γH2AX组成性表达和a-NHEJ修复选择性激活机制，以及靶向a-NHEJ修复和调节通路治疗γH2AX组成性表达弥漫大B细胞淋巴瘤的可行性。研究将丰富弥漫大B细胞淋巴瘤发病和耐药理论，发现克服耐药的新方法。

Diffuse large B-cell lymphoma (DLBCL) possesses complicated genomic aberrations which predict prognosis and result from the abnormality of DNA repair. γH2AX is a reliable marker of DNA double-strand breaks (DSB). Our preliminary study found constitutive expression of γH2AX in one half of new-diagnosed patients and its independent association with poor prognosis after immunochemothrapy; the study using gene array revealed these patients having a distinctive gene expression profiling and higher level of a-NHEJ repair components; in in-vitro cell line assays, γH2AX expression was confirmed to have a positive relevance to doxorubicin resistance and PARP1 inhibitor can overcame the resistance. Therefore, we infer that DLBCL with constitutive γH2AX expression should be considered as an important subset and the activation of a-NHEJ repair plays a critical role in the pathogenesis and resistance. This project will further explore the mechanisms of constitutive γH2AX expression and alternative activation of a-NHEJ repair, and the feasibility of targeting a-NHEJ repair and its regulating signaling pathways as novel therapeutic approaches. The investigation will be performed in tumor tissues, cell lines and mouse models using methods of molecular biology and proteomics. The study is expected to provide new insight into the pathogenesis and resistance of DLBCL and discover novel approaches to overcome resistance.