PLX127633

GSE113070: Role of Epstein-Barr Virus (EBV) latency protein EBNA3C in EBV-induced lymphomagenesis in a cord blood-humanized mouse model

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

This study compares cellular and viral gene expression in a cord blood-humanized (CBH) mouse model infected with wild-type Epstein-Barr virus (WT), versus a mutant EBV deleted in the latent viral EBNA3C gene (3C). EBV causes human B-cell lymphomas and transforms B cells in vitro. EBNA3C, an EBV protein expressed in latently infected cells, is required for EBV transformation of B cells in vitro. However, many EBV+ lymphomas in humans do not express this protein, suggesting that it may be less important in vivo or that cellular mutations and/or signaling pathways may obviate the need for EBNA3C. EBNA3C collaborates with EBNA3A to repress expression of the CDKN2A-encoded tumor suppressors, p16 and p14, and EBNA3C-deleted EBV transforms B cells containing a p16 germline mutation in vitro. We found that the 3C virus induced fewer lymphomas (occurring with a delayed onset) in comparison to the wild-type (WT) control virus, although a subset (10/26) of 3C-infected CBH mice eventually developed invasive diffuse large B cell lymphomas with type III latency. Both WT and 3C viruses induced monoclonal B-cell lymphomas (without somatic hyper-mutation) that were infiltrated by polyclonal T cells. In comparison to WT-infected tumors, 3C-infected tumors had greatly increased p16 levels, and RNA-seq analysis revealed a decrease in E2F target gene expression. However, we found that 3C-infected tumors expressed c-Myc and cyclin E at similar levels compared to WT-infected tumors, allowing cells to at least partially bypass p16-mediated cell cycle inhibition. Unexpectedly, 3C-infected tumors had increased T-cell infiltration, increased expression of T-cell chemokines (CCL5, CCL20 and CCL22) and enhanced type I interferon response in comparison to WT tumors. Together, these results reveal that EBNA3C contributes to, but is not essential for, EBV-induced lymphomagenesis in CBH mice, and suggest potentially important immunologic roles of EBNA3C in vivo. SOURCE: Shannon,C,Kenney (jcromero@wisc.edu) - University of Wisconsin-Madison