MYC directly transactivates CR2/CD21, the receptor of the Epstein–Barr virus, enhancing the viral infection of Burkitt lymphoma cells

Abstract

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.