Abstract
Human T-cell leukemia virus type-1 (HTLV-1) is a tumorigenic retrovirus responsible for development of adult T-cell leukemia/lymphoma (ATLL). This disease manifests after a long clinical latency period of up to 2–3 decades. Two viral gene products, Tax and HBZ, have transforming properties and play a role in the pathogenic process. Genetic and epigenetic cellular changes also occur in HTLV-1-infected cells, which contribute to transformation and disease development. However, the role of cellular factors in transformation is not completely understood. Herein, we examined the role of protein arginine methyltransferase 5 (PRMT5) on HTLV-1-mediated cellular transformation and viral gene expression. We found PRMT5 expression was upregulated during HTLV-1-mediated T-cell transformation, as well as in established lymphocytic leukemia/lymphoma cell lines and ATLL patient PBMCs. shRNA-mediated reduction in PRMT5 protein levels or its inhibition by a small molecule inhibitor (PRMT5i) in HTLV-1-infected lymphocytes resulted in increased viral gene expression and decreased cellular proliferation. PRMT5i also had selective toxicity in HTLV-1-transformed T-cells. Finally, we demonstrated that PRMT5 and the HTLV-1 p30 protein had an additive inhibitory effect on HTLV-1 gene expression. Our study provides evidence for PRMT5 as a host cell factor important in HTLV-1-mediated T-cell transformation, and a potential target for ATLL treatment.
Highlights
Human T-cell leukemia virus type-1 (HTLV-1) is a tumorigenic retrovirus that infects an estimated15–20 million people worldwide [1]
We found protein arginine methyltransferase 5 (PRMT5) levels were upregulated during T-cell transformation and in established lymphocytic leukemia/lymphoma cell lines
Our data suggested that PRMT5 negatively regulated HTLV-1 viral gene expression, which indicated that PRMT5 could be an important cellular regulator of the viral transformation process
Summary
Human T-cell leukemia virus type-1 (HTLV-1) is a tumorigenic retrovirus that infects an estimated. Tax expression is lost in greater than 70% of ATLL cells due to genetic and/or epigenetic changes in the HTLV-1 provirus, which include deletion or methylation of the viral 5' LTR. These changes abolish expression of other viral genes with the exception of HBZ. The requirement for Tax and other viral proteins in vivo suggests that expression of viral proteins early in infection plays a major role in viral replication, infected cell survival, and disease development. Our data suggested that PRMT5 negatively regulated HTLV-1 viral gene expression, which indicated that PRMT5 could be an important cellular regulator of the viral transformation process. Selective inhibition of PRMT5 by a novel small molecule inhibitor (PRMT5i) in HTLV-1-positive cell lines reduced cell survival; PRMT5 may represent an important therapeutic target for ATLL
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