부산대학교 도서관

Epstein–Barr virus (EBV) encodes a wealth of oncogenic instructions, including the abilities to drive a resting normal B cell to proliferate and to override apoptotic stimuli. EBV is found in almost all types of lymphomas at varying frequencies. However, the particular viral genes expressed differ considerably among tumors. We have examined the role of EBV in several lymphomas by conditionally evicting the extrachromosomal viral genome from tumor cells in vitro and have found a graded dependence on the virus. Tumor cells that express all the known latent viral genes have been found to depend on the virus to drive proliferation and to block apoptosis at least in part by repressing the proapoptotic protein Bim. Other tumor cells, which express fewer viral genes, also depend on the virus to block apoptosis, but rely on the virus to promote but not to drive proliferation. Lastly, tumor cells with the fewest viral genes expressed have been found to require EBV to prevent the inefficient induction of a Bim-independent apoptosis. We present a model for the evolution of EBV-induced lymphomas in which tumors are initially “addicted” to the virus for almost all oncogenic functions. These tumors are targets for the immune system because they express multiple immunogenic viral proteins. Therefore, EBV-induced tumors are under selective pressure to acquire cellular mutations that can replace viral functions. We posit that the heterogeneity in viral gene expression among different EBV-associated lymphomas reflects a dynamic process by which tumors evolve to be less dependent on the virus.