Epstein-Barr virus small RNAs potentiate tumorigenicity of Burkitt lymphoma cells independently of an effect on apoptosis

The tumorigenic potential of the Burkitt lymphoma (BL) cell line Akata is d ependent on the restricted Latency program of Epstein-Barr virus (EBV) that is characteristically maintained in BL tumors. Within these cells, EBV-med iated inhibition of apoptosis correlates with an up-regulation of BCL-2 lev els in concert with a down-regulation in c-MYC expression that occurs under growth-limiting conditions. Here we addressed whether EBV's effects on apo ptosis and tumorigenicity are mediated by the EBV small RNAs EBER-1 and EBE R-2. Stable expression of the EBERs in EBV-negative Akata BL cells, at leve ls comparable to those in EBV-positive cells, significantly enhanced the tu morigenic potential of EBV-negative BL cells in SCID mice, but did not full y restore tumorigenicity relative to EBV-positive Akata cells. Furthermore, wild-type or greater levels of EBER expression in EBV-negative Akata cells did not promote BL cell survival. These data therefore suggest that EBV ca n contribute to BL through at least two avenues: an EBER-dependent mechanis m that enhances tumorigenic potential independent of a direct effect on apo ptosis, and a second mechanism, mediated by an as-yet-unidentified EBV gene (s), that offsets the proapoptotic consequences of deregulated c-MYC in BL.