Institute of Cancer and Genomic Sciences and Centre for Human Virology, University of Birmingham, College of Medical and Dental Sciences, Birmingham B15 2TT, UK.
Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, UK.
Cell Death Differ. 2018 Feb;25(2):241-254. doi: 10.1038/cdd.2017.150. Epub 2017 Sep 29.
While the association of Epstein-Barr virus (EBV) with Burkitt lymphoma (BL) has long been recognised, the precise role of the virus in BL pathogenesis is not fully resolved. EBV can be lost spontaneously from some BL cell lines, and these EBV-loss lymphoma cells reportedly have a survival disadvantage. Here we have generated an extensive panel of EBV-loss clones from multiple BL backgrounds and examined their phenotype comparing them to their isogenic EBV-positive counterparts. We report that, while loss of EBV from BL cells is rare, it is consistently associated with an enhanced predisposition to undergo apoptosis and reduced tumorigenicity in vivo. Importantly, reinfection of EBV-loss clones with EBV, but surprisingly not transduction with individual BL-associated latent viral genes, restored protection from apoptosis. Expression profiling and functional analysis of apoptosis-related proteins and transcripts in BL cells revealed that EBV inhibits the upregulation of the proapoptotic BH3-only proteins, BIM and PUMA. We conclude that latent EBV genes cooperatively enhance the survival of BL cells by suppression of the intrinsic apoptosis pathway signalling via inhibition of the potent apoptosis initiators, BIM and PUMA.
虽然爱泼斯坦-巴尔病毒（EBV）与伯基特淋巴瘤（BL）的关联早已被认识，但病毒在 BL 发病机制中的确切作用尚未完全解决。EBV 可自发地从一些 BL 细胞系中丢失，据报道，这些 EBV 丢失的淋巴瘤细胞具有生存劣势。在这里，我们从多个 BL 背景中生成了广泛的 EBV 缺失克隆，并对其表型进行了比较，与它们的同基因 EBV 阳性对照进行了比较。我们报告说，虽然 BL 细胞中 EBV 的丢失很少见，但它总是与凋亡的易感性增强和体内肿瘤形成能力降低有关。重要的是，用 EBV 重新感染 EBV 缺失克隆，而不是用单个 BL 相关潜伏病毒基因转导，恢复了对凋亡的保护。对 BL 细胞中与凋亡相关的蛋白质和转录物的表达谱和功能分析表明，EBV 通过抑制强效凋亡起始子 BIM 和 PUMA 的表达，抑制内在凋亡途径信号转导，从而抑制凋亡。我们的结论是，潜伏的 EBV 基因通过抑制强效凋亡起始子 BIM 和 PUMA 的表达，协同增强 BL 细胞的存活。
