High levels of LINE-1 transposable elements expressed in Kaposi's sarcoma-associated herpesvirus-related primary effusion lymphoma

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV, HHV-8) is a gamma herpesvirus associated with several human malignancies. Transposable elements (TEs) are ubiquitous in eukaryotic genomes, occupying about 45% of the human genome. TEs have been linked with a variety of disorders and malignancies, though the precise nature of their contribution to many of them has yet to be elucidated. Global transcriptome analysis for differentially expressed TEs in KSHV-associated primary effusion lymphoma (PEL) cells (BCBL1 and BC3) revealed large number of differentially expressed TEs. These differentially expressed TEs include LTR transposons, long interspersed nuclear elements (LINEs), and short interspersed nuclear elements (SINEs). Further analysis of LINE-1 (L1) elements revealed expression upregulation, hypo-methylation, and transition into open chromatin in PEL. In agreement with high L1 expression, PEL cells express ORF1 protein and possess high reverse transcriptase (RT)-activity. Interestingly, inhibition of this RT-activity suppressed PEL cell growth. Collectively, we identified high expression of TEs, and specifically of L1 as a critical component in the proliferation of PEL cells. This observation is relevant for the treatment of KSHV-associated malignancies since they often develop in AIDS patients that are treated with RT inhibitors with potent inhibition for both HIV and L1 RT activity.