LINE-1 reverse transcriptase controls proliferation and gene expression in KSHV-associated primary effusion lymphoma

Kaposi’s sarcoma associated herpesvirus (KSHV, HHV-8) is the causative agent of all forms of Kaposi’s sarcoma (KS) and is tightly associated with primary effusion lymphoma (PEL), and multicentric Castleman’s disease. Latently infected cells, including KSHV-associated PEL cells, express many dysregulated cellular genes and miRNAs. The Long Interspersed Nuclear Element -1 (LINE-1, L1) is the most abundant transposable element, occupying 17% of the human genome. Since it is still able to transpose, L1 expression is tightly controlled, and generally repressed in somatic cells. Up-regulation of L1 can be detected in many cancers, and inhibition of L1 encoded reverse transcriptase (RT) modulates gene expression and inhibits cancer cells proliferation. We have found high L1 expression, 5’UTR promoter hypo-methylation and transition into open chromatin in PEL. In de-novo KSHV-infected BJAB cells we also detected up-regulation of L1, although to a lesser extent. In agreement with high L1 expression, PEL cells express ORF1 protein and possess high RT-activity. Interestingly, inhibition of this RT-activity suppressed PEL cell growth. Considering the effect of L1 RT on cellular miRNA and gene expression, we asked for the contribution of L1 RT for the gene expression observed in KSHV-infected cells. We inhibited L1 RT in PEL cells and performed global analysis of miRNA (miRNA-seq) and mRNA (RNA-seq). We identified about 120 genes, that their high expression in PEL is dependent on L1 RT. We propose that L1 RT modulates gene expression leading to lose of cell identity and high proliferation that can be reversed by RT inhibition.