The curious case of the tumour virus: 50 years of Burkitt's lymphoma

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Abstract
Epstein–Barr virus (EBV) was discovered in Burkitt's lymphoma (BL), a tumour with some characteristics of germinal centre (GC) B lymphocytes, which led to the proposal that EBV was the first candidate human tumour virus. Subsequently, evidence accrued to support this notion, including the important fact that EBV could transform B lymphocytes in tissue culture (the growth transcription programme). The 'EBV as BL tumour virus' hypothesis became confounded by a number of findings. These included the discovery that BL could occur without EBV, the fact that it was the deregulation of the cellular oncogene MYC through a translocation that was the defining defect in BL and that none of the EBV-transforming proteins was expressed in BL. EBV was found to persist quiescently in resting, GC-derived memory B cells, in which none of the viral transforming proteins was expressed, just like BL. Consequently, a new model of EBV persistence was developed in which EBV used the growth transcription programme to transiently activate newly infected B cells so they could differentiate via the GC into the memory compartment. It was established that deregulation of MYC by translocation not only drives proliferation but also induces apoptosis — this serves as a rate-limiting step in lymphomagenesis. Gene-regulation experiments on the viral EBNA3 (EBV nuclear antigen 3) proteins revealed that they may play a part in transition from the growth programme through the GC and into memory. In parallel, they may epigenetically alter the cellular genome in such a way as to allow the infected cell to tolerate apoptosis caused by a deregulated MYC gene long after the viral genes cease expression. The translocation event probably occurs in the GC, driven by AID (activation-induced cytidine deaminase) expression after the viral-transforming genes have been turned off. This cell then exits from the GC in an attempt to become a resting memory B cell, but is unable to do so because deregulated MYC keeps it proliferating. Malaria is associated with the high incidence of EBV-positive BL in tropical Africa, but we know nothing about the underlying mechanism of this association. Malaria may increase both the frequency of spontaneous MYC translocations and the number of EBV-infected cells, thereby dramatically increasing the possibility that both MYC and EBV will occur in the same cell and lead to BL.