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Role of protein arginine methyltransferase 5 over-expression in HTLV-1-driven cellular transformation and leukemia

Human T-cell leukemia virus -1 (HTLV-1) is a delta retrovirus that infects an estimated 15-25 million people worldwide. HTLV-1 is the causative infectious agent of adult T-cell leukemia/lymphoma (ATL) and a neurodegenerative disease (HAM/TSP). While the probability of presenting any symptoms related to HTLV-1 infection is relatively low (roughly 5-10% for the lifetime of an infected individual), the disease progression and prognosis of those infected individuals who develop ATL is fatal, with a median survival range of 8-10 months. Unfortunately, ATL is highly chemotherapy resistant and while many current therapies improve ATL patient survival, the patients consistently relapse. Therefore, a need exists to develop treatments that improve ATL outcome. We have recently identified PRMT5 (protein arginine methyltransferase 5) as a potential target to modulate HTLV-1 gene expression. We find that PRMT5 protein levels are elevated in T-cell leukemia/lymphoma cell lines compared to freshly isolated naïve T-cells. PRMT5 RNA levels do not correlate to PRMT5 protein levels, suggesting a possible post-transcriptional method of regulation. Furthermore, we also show that PRMT5 protein expression is slightly elevated during short-term immortalization, but gains highest expression after transformation and IL-2 independence. Utilizing shRNA vectors, we demonstrate that knockdown of endogenous PRMT5 results in a decrease in viral p19 production in a HTLV-1-transformed cell line. Finally, we observe a decrease in cell proliferation and in viral gene expression when HTLV-1-infected/-transformed cells are treated with a novel small molecule inhibitor of PRMT5. In conclusion, we find PRMT5 to be a positive regulator of HTLV-1 gene expression.

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Correspondence to Patrick L Green.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( https://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated.

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Panfil, A.R., Al-Saleem, J.J., Baiocchi, R.A. et al. Role of protein arginine methyltransferase 5 over-expression in HTLV-1-driven cellular transformation and leukemia. Retrovirology 11, O65 (2014). https://doi.org/10.1186/1742-4690-11-S1-O65

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Keywords

  • Leukemia
  • Neurodegenerative Disease
  • Infected Individual
  • Molecule Inhibitor
  • Leukemia Virus