Abstract B30: EBV LMP2A bypasses p53 inactivation in a MYC model of lymphomagenesis

Abstract

Abstract Although Epstein-Barr virus (EBV) is linked to Burkitt's lymphoma (BL), the role of the virus in lymphomagenesis is unclear. LMP2A, encoded by EBV, is detected in BL biopsies and has pro-survival functions. We generated mice expressing MYC and LMP2A in B cells. Pretumor LMP2A/λ-MYC mice have significantly enlarged spleen size. In addition, LMP2A/λ-MYC mice show greatly accelerated tumor onset compared to λ-MYC mice. Inactivation of the p53 pathway and failure to induce the pro-apoptotic BH3-only protein, BIM are two major paths to tumor formation in MYC tumor models. Similar to previous work, we found p53 mutations in λ-MYC tumors, however we detected no p53 mutations in the rapidly arising LMP2A/λ-MYC tumors. We further demonstrate that the p53 pathway is functionally intact in LMP2A/λ-MYC tumors, which show increased levels of PUMA and sensitivity to p53 activation by Nutlin. We also show that BIM is induced in LMP2A/λ-MYC tumor cells. Despite the presence of p53 mutations in EBV+ human BL, our mouse model can be used to understand BL development in humans. We believe that LMP2A is important early in lymphomagenesis. The pro-survival function of LMP2A leads to an initial expansion of cells that have acquired a MYC translocation. This expansion is shown in our mouse model by enlarged spleens in pre-tumor mice. In humans, early expansion of cells increases the probability that a p53 mutation will occur in a cell with translocated MYC. Once the p53 mutation occurs, weak immune surveillance may select against high levels of LMP2A, consistent with low levels of LMP2A transcripts found in tumor biopsies. We have identified a novel mechanism that permits lymphomagenesis in the presence of an intact p53 pathway. This work also uncovers a contribution of Epstein-Barr virus (EBV) to molecular events that have documented importance in BL pathogenesis, and may underlie the poorly understood link between EBV and BL. Citation Information: Cancer Res 2009;69(23 Suppl):B30.