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.
Human T-cell leukemia virus type 1 (HTLV-1) infects approximately 15 to 25 million people worldwide and is the causative infectious agent of adult T-cell leukemia/ lymphoma (ATL). ATL arises after an extensive clinical latency period; however the detailed mechanism(s) of ATL development remain poorly defined. Here we focus on PRMT5 (protein arginine methyltransferase 5), an epigenetic player involved in cellular transformation and silencing tumor suppressor gene expression. Understanding the role of PRMT5 during HTLV-1-driven cellular transformation and leukemia will have significant implications for therapeutic targeting of this protein and towards understanding the genetic and epigenetic changes that arise during ATL development.
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