Detection of Epstein-Barr virus (EBV) in Burkitt’s lymphoma (BL) tumor cells more than 45 years ago brought about discovery of EBV, and was important in revealing a link between viruses and cancer. However, a mechanistic role for EBV in BL development or progression has still not been identified. Latent membrane protein 2A (LMP2A) is an EBV latency protein expressed in all EBV-associated malignancies, and is one of few viral proteins that can be detected in BL biopsies. In the absence of an animal model for EBV infection or latency, LMP2A transgenic mouse models in which LMP2A is expressed in B cells have been useful for demonstrating the ability of LMP2A to provide a survival signal in vivo. LMP2A/λ- MYC mice were generated by crossing LMP2A transgenic mice with a transgenic line in which the proto-oncogene MYC is expressed from the immunoglobulin lambda promoter, representing the translocation of MYC to an immunoglobulin locus that is required for BL tumorigenesis. In comparison to λ- MYC mice, LMP2A/λ-MYC mice have accelerated onset of lymph node tumors. Inactivation of the major tumor suppressor p53 is common in tumors from MYC transgenic mice and in human BL tumors. Accordingly, p53 mutations were frequently detected in tumors from λ-MYC mice, but no mutations in p53 could be detected in LMP2A/λ- MYC tumors. Further, the p53 pathway is functionally intact in LMP2A/λ- MYC tumor cells. The LMP2A/λ-MYC mouse model represents a novel mechanism for MYC-induced tumorigenesis in the presence of an intact p53 pathway. Despite differences in p53 status, analysis of total gene expression in LMP2A/λ-MYC and λ- MYC tumors revealed that these two tumor types are transcriptionally very similar. In contrast, gene expression in B cells from 3 week old LMP2A/λ- MYC and λ-MYC mice is quite different. Taken together, these data support a model in which LMP2A is important early in tumorigenesis, counteracting tumor suppressive pathways induced by deregulated MYC to allow for tumor progression. After tumor progression, it is proposed that LMP2A is no longer necessary and may be targeted by a weak immune response, resulting in low level expression in tumor biopsies.