Coordinated repression of BIM and PUMA by Epstein-Barr virus latent genes maintains the survival of Burkitt lymphoma cells

Leah Fitzsimmons, Andrew J Boyce, Wenbin Wei, Catherine Chang, Deborah Croom-Carter, Rosemary J Tierney, Marco J Herold, Andrew I Bell, Andreas Strasser, Gemma L Kelly, Martin Rowe

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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.Cell Death and Differentiation advance online publication, 29 September 2017; doi:10.1038/cdd.2017.150.

Original languageEnglish
JournalCell Death & Differentiation
Early online date29 Sept 2017
Publication statusE-pub ahead of print - 29 Sept 2017


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