title: PRMT5 Is Upregulated in HTLV-1-Mediated T-Cell Transformation and Selective Inhibition Alters Viral Gene Expression and Infected Cell Survival.
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.
authors.affiliation: Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA. panfil.6@osu.edu.|Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA. panfil.6@osu.edu.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Panfil
authors.affiliation: Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA. al-saleem.1@osu.edu.|Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA. al-saleem.1@osu.edu.
authors.forename: Jacob
authors.initials: J
authors.lastname: Al-Saleem
authors.affiliation: Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA. howard.937@osu.edu.|Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA. howard.937@osu.edu.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Howard
authors.affiliation: Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210, USA. mates.6@osu.edu.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Mates
authors.affiliation: Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA. kwiek.2@osu.edu.|Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210, USA. kwiek.2@osu.edu.|Department of Microbiology and Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA. kwiek.2@osu.edu.
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Kwiek
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA. baiocchi.1@osu.edu.|Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA. baiocchi.1@osu.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Baiocchi
authors.affiliation: Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA. green.466@osu.edu.|Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA. green.466@osu.edu.|Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA. green.466@osu.edu.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Green
mesh_terms: D002470:Cell Survival; D002472:Cell Transformation, Viral; D015967:Gene Expression Regulation, Viral; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016356:Gene Products, tax; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: ATLL; HBZ; HTLV-1; PRMT5; Tax; lymphoma; p30; transformation