EBV BCL-2 homologue BHRF1 drives chemoresistance and lymphomagenesis by inhibiting multiple cellular pro-apoptotic proteins

Leah Fitzsimmons, Rachael Cartlidge, C. Chang, Nenad Sejic, L. C. A. Galbraith, C. D. Suraweera, Deborah Croom-Carter, G. Dewson, Rosemary Tierney, Andrew Bell, Claire Shannon-Lowe, Marco Herold, Alan Rickinson, P. M. Colman, D. C. S. Huang, Andreas Strasser, Mark Kvansakul, Martin Rowe, Gemma L. Kelly

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


Epstein-Barr virus (EBV), which is ubiquitous in the adult population, is causally associated with human malignancies. Like many infectious agents, EBV has evolved strategies to block host cell death, including through expression of viral homologues of cellular BCL-2 pro-survival proteins (vBCL-2s), such as BHRF1. Small molecule inhibitors of the cellular pro-survival BCL-2 family proteins, termed 'BH3-mimetics', have entered clinical trials for blood cancers with the BCL-2 inhibitor venetoclax already approved for treatment of therapy refractory chronic lymphocytic leukaemia and acute myeloid leukaemia in the elderly. The generation of BH3-mimetics that could specifically target vBCL-2 proteins may be an attractive therapeutic option for virus-associated cancers, since these drugs would be expected to only kill virally infected cells with only minimal side effects on normal healthy tissues. To achieve this, a better understanding of the contribution of vBCL-2 proteins to tumorigenesis and insights into their biochemical functions is needed. In the context of Burkitt lymphoma (BL), BHRF1 expression conferred strong resistance to diverse apoptotic stimuli. Furthermore, BHRF1 expression in mouse haematopoietic stem and progenitor cells accelerated MYC-induced lymphoma development in a model of BL. BHRF1 interacts with the cellular pro-apoptotic BCL-2 proteins, BIM, BID, PUMA and BAK, but its capability to inhibit apoptosis could not be mapped solely to one of these interactions, suggesting plasticity is a key feature of BHRF1. Site-directed mutagenesis revealed a site in BHRF1 that was critical for its interaction with PUMA and blocking DNA-damage-induced apoptosis, identifying a potentially therapeutically targetable vulnerability in BHRF1.
Original languageEnglish
Pages (from-to)1554-1568
Number of pages15
JournalCell Death & Differentiation
Issue number5
Publication statusPublished - 23 Oct 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'EBV BCL-2 homologue BHRF1 drives chemoresistance and lymphomagenesis by inhibiting multiple cellular pro-apoptotic proteins'. Together they form a unique fingerprint.

Cite this