EB病毒在慢性淋巴细胞白血病Richter转化中的作用机制研究

Richter’s syndrome (RS) described the development of a secondary aggressive lymphoma, most of which was diffuse large B-cell lymphoma (RS-DLBCL), in patients with chronic lymphoma (CLL)/small lymphocytic lymphoma (SLL). The pathologenesis of RS transformation is still unclear. Epstien-Barr virus (EBV) is a ubiquitous herpes virus, which has been closely associated with the pathogenesis of several kinds of tumors, and it is also tighly associated with RS transformation. We have found that CLL/SLL patients were all latently infected by EBV and 37.5% of RS-DLBCL patients had elevated EBV-DNA copy number in the whole blood. Furthermore, we have also examined EBV-DNA in the tumor cells of RS-DLBCL patients. The project intends to further investigate the latency infection program, the EBV-encoded microRNA (EBV-miRNAs) expression profile, and the exactly pathogenetical roles of EBV which were from two aspects: EBV-miRNAs (ebv-miR-BART5 tagerts regulating PUMA and ebv-miR-BART22 targets regulating Caspase3 in pathways of apoptosis) and EBV nuclear antigen (EBNA2 tagerts regulating miR-21/PTEN/PI3K/Akt singaling pathway), to explore the role of EBV in Richter transformation of CLL and to provide new targets therapy of RS-DLBCL.

Richter’s综合征（RS）是指慢性淋巴细胞白血病（CLL）向侵袭性淋巴瘤转化，其中向弥漫大B细胞淋巴瘤（DLBCL）转化（RS-DLBCL）最常见，其转化机制尚不清楚。EB病毒（EBV）与多种肿瘤发生发展相关，与CLL的RS转化也有密切关系。我们前期研究发现CLL患者既往均曾感染EBV，37.5%的RS-DLBCL患者外周血EBV-DNA载量增高，且在部分RS肿瘤细胞中检测出EBV。本课题拟进一步明确RS-DLBCL中EBV潜伏感染类型及EBV编码微小RNA（EBV-miRNAs）表达谱，从EBV-miRNAs (ebv-miR-BART5对PUMA调控、ebv-miR-BART22对Caspase 3调控）和EBV编码蛋白（EBNA2对miR-21/PTEN/PIK3K/Akt信号通路调控）入手，探索EBV在CLL Richter转化中的作用机制，为开展相应的靶向治疗提供新思路。

Richter’s综合征（RS）是指慢性淋巴细胞白血病（CLL）或小淋巴细胞淋巴瘤（SLL）向侵袭性淋巴瘤转化，其中向弥漫大B细胞淋巴瘤（DLBCL）转化（RS-DLBCL）最为常见。EB病毒（EBV）参与多种肿瘤的发生和发展相关，与CLL/SLL的RS转化也有密切关系。我们研究发现：（1）CLL患者中全血EBV-DNA与预后相关，且具有动态预测的价值；（2）ebv-miR-BHRF1-1高表达的CLL患者总生存时间较短；（3）在CLL细胞中EBV-miR-BHRF1-1与p53基因存在正反馈调控；（4）PUMA是EBV-miR-BART5-5p靶基因，且EBV-miR-BART5-5p可以促进EBV阳性DLBCL肿瘤细胞生长；（5）CLL患者中PUMA和PTEN的表达具有预后价值；（6）在EBV阳性的DLBCL中，EBV-miR-BART5-5p不仅可以通过直接靶向 PUMA 3'UTR 来下调PUMA表达，还可以通过影响细胞质中p53非依赖途径进一步抑制PUMA的表达；（7）EBV-miR-BART5-5p可降低EBV阳性DLBCL细胞对多柔比星的敏感性。通过本研究揭示了EBV在CLL中的生物学特性和功能，以及EBV相关的miRNAs（EBV-miR-BHRF1-1和EBV-miR-BART5-5p）在CLL/SLL转化的EBV阳性的DLBCL过程中的潜在的作用机制，为CLL转化的EBV阳性的DLBCL个体化治疗提供新的思路。