No abstract

The molecular hallmark of Burkitt lymphoma (BL) is a chromosomal translocation that results in deregulated expression of MYC oncogene. 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 to CR2 downregulation both in proliferating and in arrested cells. Second, MYC binds human CR2 promoter and this binding depends on E-box elements. Third, MYC activates CR2 promoter in an E-box dependent manner. Four, MYC activates CR2 transcription in the absence of protein synthesis. Importantly, MYC also induces CR2 expression in mouse primary B cells. Thus, CR2 is a bona fide MYC 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.

MYC is an oncogenic transcription factor dysregulated in about half of total human tumors. Transcriptomic studies reveal more than 1000 genes regulated by MYC but a much smaller fraction of genes is directly transactivated by MYC. Virtually all Burkitt lymphoma (BL) carry chromosomal translocations involving MYC oncogene. All endemic BL and a fraction of sporadic BL are associated to Epstein-Barr virus (EBV) infection. The currently accepted mechanism is that EBV is the lymphoma causing agent inducing MYC translocation. Herein we show that the EBV receptor gene, CR2 (or CD21), is a bona fide direct MYC target gene. This is based on several evidences: MYC induces CR2 expression in both proliferating and arrested cells, binds the human CR2 promoter and transactivates CR2 in an E-box dependent manner and in the absence of protein synthesis. Moreover, using mice with conditional MYC ablation we show that MYC induces CR2 in primary B cells. Importantly, MYC silencing or MYC overexpression in BL cells results in less and more efficient EBV infection, respectively. Altogether, in contrast to the widely accepted mechanism for the correlation between EBV and endemic BL, we propose an alternative mechanism in which MYC dysregulation occurs first and favors the EBV infection.