Understanding the evolution of lymphomas induced by Epstein-Barr virus

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 multiple apoptotic stimuli. EBV is found in almost all types of lymphomas at varying frequencies. However, the particular set of viral genes expressed differs considerably among tumors. I have examined the role of EBV in several lymphomas by conditionally evicting the extrachromosomal viral genome from tumor cells in vitro. I found that there exists a graded dependence on EBV among different tumor cells. Post-transplant lymphoproliferative disorder (PTLD) tumors arise under severe clinical immunosuppression, can be found to contain a normal karyotype, and often express a full battery of latent viral genes. These tumor cells depend on the virus to drive cells out of G1/G0 and to block the induction of apoptosis at least in part by repressing the pro-apoptotic protein Bim. In contrast, Burkitt's lymphomas (BL) arise after immunosuppression resulting from acute malarial infection, contain defined cellular mutations, and express fewer viral genes. Cells of a subset of these tumors, Wp-restricted BLs, like PTLDs, depend on the virus to block an apoptotic program that involves Bim. However, unlike PTLDs, Wp-restricted BL cells rely on the virus to promote but not drive proliferation. The majority of Burkitt's lymphomas, canonical Burkitt's, express even fewer viral genes than do Wp-restricted BLs. These tumor cells have the least dependence on the virus some require EBV to prevent the inefficient induction of a Bim-independent apoptosis. I found that EBV provides this selective advantage to canonical BL cells, at least in part, through the viral BART miRNAs. I 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 prime 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. I posit that the broad 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.