Coordinated repression of BIM and PUMA by Epstein-Barr virus latent genes maintains the survival of Burkitt lymphoma cells
Coordinated repression of BIM and PUMA by Epstein-Barr virus latent genes maintains the survival of Burkitt lymphoma cells
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DOI：
10.1038/cdd.2017.150
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发表时间：
2018-02-01
影响因子：
12.4
通讯作者：
Rowe, Martin
中科院分区：
文献类型：
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作者：
Fitzsimmons, Leah;Boyce, Andrew J.;Rowe, Martin
虽然爱泼斯坦-巴尔病毒(EBV)与Burkitt淋巴瘤(BL)的关系早已被认识到，但该病毒在Burkitt淋巴瘤发病机制中的确切作用尚未完全解决。EBV可以从一些BL细胞系中自发地丢失，据报道，这些EBV丢失的淋巴瘤细胞具有生存劣势。在这里，我们生成了一个来自多个BL背景的EBV丢失克隆的广泛小组，并检查了它们的表型，将它们与同基因EBV阳性克隆进行了比较。我们报告，虽然从BL细胞中丢失EBV的情况很少见，但它始终与体内发生凋亡的易感性增强和肿瘤致瘤性降低有关。重要的是，用EBV再次感染EBV缺失克隆，但令人惊讶的是，没有转导个别与BL相关的潜伏病毒基因，恢复了对细胞凋亡的保护。凋亡相关蛋白和转录本的表达谱和功能分析表明，EBV抑制了促凋亡的BH3蛋白BIM和PUMA的上调。我们的结论是，潜伏的EBV基因通过抑制强大的凋亡启动子BIM和PUMA来抑制内在的凋亡途径信号，从而协同提高BL细胞的存活率。
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.