EBV-B cell interactions: immortalization, rescue from apoptosis, tumorigenicity (a short review)

Translocation of the c-myc gene to an immunoglobulin locus is a rate-limiting step in the genesis of three B-cell derived tumors: Burkitt lymphoma (BL) in humans, mouse plasmacytoma (MPC) and rat immunocytoma. Its consequences have been best analyzed in BL. They involve a non-immunological and an immunological component. The former acts by preventing the B cell from leaving the cycling compartment and entering the resting stage when programmed to do so. The latter acts by the down regulation of certain HLA class I polymorphic specificities, adhesion molecules and EBV encoded proteins. According to our interpretation, the translocation fixes the BL cell in a phenotypic window that can be referred to as "a resting cell that is not resting". The linking of c-myc to immunoglobulin sequences in a B cell leads to constitutive myc expression. In spite of its switch to a "resting phenotype", the cell is therefore unable to leave the cycling compartment. Normally, EBV-carrying B-blasts face immune controls. They can only proliferate in immunodefectives, as in XLP or transplant lymphoma. Due to its "resting" rather than B-blast phenotype and the correlated defective expression of certain EBV, HLA and adhesion molecules, the BL cell is not rejected by the EBV-specific immune response, however. The down-regulation of EBNA 2-6 in the BL cell may be also considered in relation to viral latency. The exclusive expression of EBNA 1 in the BL cell reflects the adaptation of the virus to prolonged persistence in long lived resting B cells, an important if not exclusive reservoir of the latent virus. Normal B cells that fail to be activated by appropriate mitogens or antigens within a limited period of time undergo apoptosis, as a rule. EBV may protect resting B cells. The role of the only virally encoded protein they are known to express, EBNA 1, remains to be explored in this respect. EBV infected immunoblasts are protected from apoptosis by the LMP 1 induced elevation of bcl-2 expression. During the lytic cycle when cellular protein synthesis is switched off by the early viral proteins, a member of the early protein group, a bcl-2 homologous protein encoded by the BHRF1 gene, takes over the function to protect against untimely apoptosis.