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

Oncogene volume 40, pages 536–550 (2021)Cite this article

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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.

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Fig. 1: High expression of LINE-1 in PEL cells.
Fig. 2: Expression of LINE-1 specific loci in PEL cells.
Fig. 3: Dysregulation of ERVs in PEL cells.
Fig. 4: Expression of ERVs specific loci in PEL cells.
Fig. 5: Hypo-methylation and open histone marks at LINE-1 in PEL cells.
Fig. 6: Dysregulation of TEs in KSHV de novo infected BJAB.219 cells.
Fig. 7: RT-inhibitors inhibit PEL cell proliferation.

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Data availability

RNA-seq data are available at http://biodb.md.biu.ac.il/biu/shamay_lab_data.html. Supplementary Information is available at the Oncogenes’s website.

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Acknowledgements

We would like to thank S. Diane hayward, Richard F. Ambinder, Jeffrey Vieira, Shou-Jiang (SJ) Gao, Milana Frenkel-Morgenstern, and Ronit Sarid for cell lines. This work was supported by grants from the Israel Science Foundation (https://www.isf.org.il) (1134/16), the Israel Cancer Association (20150095, 20161143) funded by the Walter Bela foundation, and a Research Career Development Award from the Israel Cancer Research Fund (https://www.icrfonline.org/) (01282) to MS. We are grateful for the support of the Elias, Genevieve, and Georgianna Atol Charitable Trust to the Daniella Lee Casper Laboratory in Viral Oncology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.

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  1. These authors contributed equally: Anuj Ahuja, Guy Journo

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  1. Daniella Lee Casper Laboratory in Viral Oncology, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel

    Anuj Ahuja, Guy Journo, Ron Eitan & Meir Shamay

  2. Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84105, Beer-Sheva, Israel

    Eitan Rubin

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Ahuja, A., Journo, G., Eitan, R. et al. High levels of LINE-1 transposable elements expressed in Kaposi’s sarcoma-associated herpesvirus-related primary effusion lymphoma. Oncogene 40, 536–550 (2021). https://doi.org/10.1038/s41388-020-01549-9

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