Epstein-Barr virus regulates c-MYC, apoptosis, and tumorigenicity in Burkitt lymphoma

Loss of the Epstein-Barr virus (EBV) genome from Akata Burkitt lymphoma (BL ) cells is coincident,vith a loss of malignant phenotype, despite the fact that Akata and other EBV-positive BL cells express a restricted set of EBV gene products (type I latency) that are not known to overtly affect cell gr owth. Here we demonstrate that reestablishment of type I latency in EBV-neg ative Akata cells restores tumorigenicity and that tumorigenic potential co rrelates with an increased resistance to apoptosis under growth-limiting co nditions. The antiapoptotic effect of EBV was associated with a higher leve l of Bcl-2 expression and an EBV-dependent decrease in steady-state levels of c-MYC protein. Although the EBV EBNA-1 protein is expressed in all EBV-a ssociated tumors and is reported to have oncogenic potential, enforced expr ession of EBNA-1 alone in EBV-negative Akata cells failed to restore tumori genicity or EBV-dependent down-regulation of c-MYC. These data provide dire ct evidence that EBV contributes to the tumorigenic potential of Burkitt ly mphoma and suggest a novel model whereby a restricted latency program of EB V promotes B-cell survival, and thus virus persistence within an immune hos t, by selectively targeting the expression of c-MYC.