MYC directly transactivates CR2/CD21, the receptor of the Epstein-Barr virus, and enhances the viral infection of Burkitt lymphoma cells

Abstract

AbstractThe molecular hallmark of Burkitt lymphoma (BL) is a chromosomal translocation that results in deregulated expression ofMYConcogene. This translocation is present in virtually all BL. MYC is an oncogenic transcription factor deregulated in about half of total human tumors, by translocation or other mechanisms. Transcriptomic studies reveal more than 1000 genes regulated by MYC but a much smaller fraction of these genes is directly activated by MYC. All the endemic BL and many sporadic BL cells are associated to the Epstein-Barr virus (EBV) infection. The currently accepted mechanism for the MYC and BL association is that EBV is the causing agent inducing MYC translocation. Complement receptor 2 or CR2 (also called CD21) is a membrane protein that serves as EBV receptor in lymphoid cells. Here we show that CR2 is a direct MYC target gene. This conclusion is based on several evidences. First, MYC downregulation is linked toCR2downregulation both in proliferating and in arrested cells. Second, MYC binds humanCR2promoter and this binding depends on E-box elements. Third, MYC activatesCR2promoter in an E-box dependent manner. Four, MYC activatesCR2transcription in the absence of protein synthesis. Importantly, MYC also inducesCR2expression in mouse primary B cells. Thus, CR2 is abona fideMYC direct target gene. Moreover, higher MYC expression levels in Burkitt lymphoma-derived cells result in a more efficient EBV infection. We propose an alternative mechanism compatible with the correlation between EBV infection and MYC translocation observed in endemic BL, i.e., that deregulated MYC in BL cells occurs first and favors the EBV infection.