Epstein-Barr virus latent membrane protein 1 increases genomic instability through Egr-1-mediated up-regulation of activation-induced cytidine deaminase in B-cell lymphoma.

Epstein-Barr virus (EBV)-encoded latent membrane protein-1 (LMP1) is a transmembrane protein essential for EBV-induced immortalization and transformation of B cells. Activation-induced cytidine deaminase (AID) triggers somatic hypermutation and recombination, in turn contributing to lymphomagenesis. Here, we report an intracellular mechanism by which LMP1 contributes to B cell lymphomagenesis via AID expression. In our experiments, LMP1 increased AID mRNA expression and promoter activity. The AID promoter region contains a binding site for Egr-1, a prominent transcription factor that is reported to be up-regulated by LMP1. In promoter activity analysis, Egr-1 enhanced the reporter activity of the wild-type AID promoter, but not that containing a mutated Egr-1 binding site. Egr-1 knockdown abrogated LMP-1-mediated up-regulation of AID promoter reporter activity in EBV-negative BJAB cells and reduced AID promoter reporter activity in EBV-positive SKW6.4 cells. AID induced down-regulation of the nuclear factor-κB (NFκB) inhibitory tumor suppressor Rassf6, suggesting that AID functions as an upstream regulator of the NFκB inhibitory Rassf6. Moreover, Egr-1 expression was associated with an increased number of genomic lesions in genome-wide analysis using single nucleotide polymorphism (SNP) microarray and copy number variation (CNV). Collectively, LMP1 induces AID up-regulation and genomic instability via Egr-1. Increased AID expression may, in turn, promote down-regulation of the NFκB inhibitor, Rassf6, thereby further increasing the survival of genetically destabilized B-cell lymphoma cells.