Epstein-Barr virus (EBV) was the first virus to be aetiologically linked to human cancer, and yet the mechanisms of viral oncogenesis remain incompletely understood. Burkitt lymphoma (BL) is the commonest paediatric lymphoma in sub-Saharan Africa and was the first malignancy to be associated with EBV infection. BL tumours are extremely aggressive, a characteristic driven by the oncogene c-myc which is chronically active in BL due to a reciprocal chromosomal translocation with immunoglobulin loci. Deregulated c-myc can stimulate cell proliferation, but also sensitises BLs to apoptotic stimuli under stress conditions. EBV’s role in BL is not fully understood, partly because EBV’s full growth transforming programme is not expressed. Studies have suggested that EBV serves to protect BLs from apoptosis, thereby promoting lymphomagenesis.
Single cell cloning of BL cell lines can generate rare EBV-loss clones that are consistently more sensitive to apoptosis than their EBV-positive counterparts. Only one viral protein (EBNA1) together with a number of non-coding RNAs are reported to be expressed in BL. Our recent work has focused on determining which viral antigen confers apoptosis protection.
We have found that re-expression of EBNA1 is unable to protect EBV-loss BLs from apoptotic stimuli. Additionally, whilst the EBER RNAs of EBV have been reported to inhibit apoptosis via upregulation of IL-10, their re-expression in EBV-loss cells did not induce IL-10 expression or restore apoptosis resistance. Finally, re-expression of the two clusters of EBV BART microRNAs, that have been reported to downregulate the pro-apoptotic BH3-only protein Puma in 293 cells, did not confer any protection from apoptosis to EBV-loss BLs. Importantly however, reinfection of EBV-loss BL cells with recombinant EBV was sufficient to protect from cell death. This raises the possibilities that apoptosis resistance is conferred through the co-operation of viral genes, or through the expression of novel EBV genes with anti-apoptotic properties.