Epstein-Barr virus lytic gene BNRF1 promotes B-cell lymphomagenesis via IFI27 upregulation

Epstein-Barr virus (EBV) is a ubiquitous human lymphotropic herpesvirus that is causally associated with several malignancies. In addition to latent factors, lytic replication contributes to cancer development. In this study, we examined whether the lytic gene BNRF1, which is conserved among gamma-herpesviruses, has an important role in lymphomagenesis. We found that lymphoblastoid cell lines (LCLs) established by BNRF1-knockout EBV exhibited remarkably lower pathogenicity in a mice xenograft model than LCLs produced by wild-type EBV (LCLs-WT). RNA-seq analyses revealed that BNRF1 elicited the expression of interferon-inducible protein 27 (IFI27), which promotes cell proliferation. IFI27 knockdown in LCLs-WT resulted in excessive production of reactive oxygen species, leading to cell death and significantly decreased their pathogenicity in vivo. We also confirmed that IFI27 was upregulated during primary infection in B-cells. Our findings revealed that BNRF1 promoted robust proliferation of the B-cells that were transformed by EBV latent infection via IFI27 upregulation both in vitro and in vivo. Virus-infected cells must overcome several anti-viral host responses for stable growth. The human oncogenic herpesvirus Epstein-Barr virus (EBV) carries the genes with anti-apoptotic and proliferative functions. In this study, we demonstrated the role of the EBV protein BNRF1 in the growth resilience of B-cells infected with EBV. BNRF1 induced the expression of interferon-inducible protein 27 (IFI27), driving the proliferation of infected cells. IFI27 knockdown elicited the over production of reactive oxygen species, causing a fragile growth of both EBV-infected and EBV-transformed cells. Furthermore, disruption of the BNRF1-IFI27 axis reduced the pathogenicity of lymphoblastoid cell lines in a mouse xenograft model. These results provide insights into the neoplastic progression of EBV-infected cells and therapeutic targets against EBV-infected cells.