Role of PRMT5 in HTLV-1 transformation and disease

Ohio State University, Columbus OH

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Human T-cell leukemia virus type 1 (HTLV-1) is a human tumorigenic retrovirus that infects approximately 15-25 million people worldwide. A small portion of infected individuals fall victim to a fatal, highly chemotherapy resistant disease of CD4+ T-lymphocytes known as adult T-cell leukemia/lymphoma (ATL). Evidence suggests that ATL arises from a multitude of factors that include both genetic and epigenetic changes in the cell that accumulate over time. While many aspects of HTLV-1 biology have been revealed, the detailed mechanism(s) of ATL development remain poorly defined. Recently, our research team has identified PRMT5 over-expression to be relevant to the pathogenesis of both hematologic and solid tumors, and to play an essential role during B-cell transformation by the tumorigenic herpesvirus Epstein-Barr. PRMT5 is an epigenetic modifier that silences the transcription of many key regulatory cellular genes through symmetric di-methylation (S2Me) of arginine (R) residues on histone proteins (H4R3 & H3R8). We seek to test the hypothesis that PRMT5 contributes to HTLV-1-driven cellular transformation and leukemia, and ultimately determine the efficacy of PRMT5 inhibitors (PRMT5i) in a preclinical ATL mouse model. Specifically, we will determine 1) the expression pattern of PRMT5 protein and RNA during HTLV-1-mediated T-cell transformation using in vitro co-culture transformation assays, 2) the role of PRMT5 in host and viral gene expression using novel PRMT5i and shRNAs in tissue culture cell lines, and 3) the therapeutic effects of PRMT5i in an in vivo ATL mouse model by examining viral replication kinetics, tumor size, and survival. This R21 is a necessary first step to identify PRMT5 as an important epigenetic factor during HTLV-1-mediated cellular transformation and pathogenesis, and will ultimately provide important insight towards its potential as an ATL therapy target.