Functional Targets for Epstein-Barr Virus BART MicroRNAs in B Cell Lymphomas

MicroRNAs are key post-transcriptional regulators of gene expression and their dysregulation is often linked to cancer. Epstein-Barr virus encodes 22 BamHI A Rightward Transcript (BART) miRNAs, which are expressed in nearly all EBV-associated cancers and implicated in viral pathogenesis. To investigate biological targets for BART miRNAs in B cell lymphomas, we performed a meta-analysis of publicly available Ago-CLIP datasets from EBV-positive Burkitt lymphomas (BLs), primary effusion lymphomas (PELs), AIDS-associated diffuse large B cell lymphomas (DLBCLs), and lymphoblastoid cell lines (LCLs). Our analysis focused on comparing targets of EBV BART miRNAs across the different types of transformed B cells. Using reporter assays, we then experimentally validated over 50 functional interactions between BART miRNAs and cellular protein-coding transcripts involved in activities such as B cell differentiation (PRDM1, IRF4, and MYC), cell cycle regulation (UHMK1, CDKN1A, MDM2, and NPAT), apoptosis (MCL1), signaling and intracellular trafficking (GAB1, SOS1, MAPK1, RAB11A, CAV1, and RANBP9), and tumor suppression (CCDC6). Moreover, ectopic BART miRNA expression in several EBV-negative BL cells induced transcriptional changes that may influence molecular signatures of EBV-associated BLs. Collectively, our findings reveal novel, functional interactions for BART miRNAs in lymphomas and provide insights into their roles in these B cell cancers.