Poster abstracts
Poster number 13 submitted by Kyle Ernzen
The PRMT5 inhibitor EPZ015666 demonstrates efficacy against HTLV-1 T-cell lines in vitro and in vivo
Kyle J. Ernzen (Department of Veterinary Biosciences, Center for Retrovirus Research, The Ohio State University), Corrine Melvin, Cameron Phelps (Department of Veterinary Biosciences, Center for Retrovirus Research, The Ohio State University), Lianbo Yu (Department of Biomedical Informatics, College of Public Health, The Ohio State University), Stefan Niewiesk (Department of Veterinary Biosciences, Center for Retrovirus Research, The Ohio State University), Patrick L. Green (Department of Veterinary Biosciences, Center for Retrovirus Research, The Ohio State University), Amanda R. Panfil (Department of Veterinary Biosciences, Center for Retrovirus Research, The Ohio State University)
Abstract:
Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus and the causative agent of adult T-cell leukemia (ATL), a highly aggressive and fatal malignancy of CD4+ T-cells. Given that ATL lacks an effective long-term therapy regimen, there is an urgent need to characterize novel therapeutic targets for infected patients. Protein arginine methyltransferase 5 (PRMT5) is a type II PRMT enzyme that has been directly implicated in the tumorigenesis of several different lymphomas through the transcriptional regulation of relevant oncogenes. Our group recently demonstrated that PRMT5 RNA and protein is overexpressed in HTLV-1-transformed T-cell lines, during HTLV-1-mediated T-cell transformation, and in ATL patient samples. The primary goal of this study was to assess how PRMT5 activity impacts HTLV-1 infected cell viability, transformation, and disease pathogenesis. Small molecule-mediated inhibition of PRMT5 enzymatic activity with a commercially available inhibitor (EPZ015666) resulted in selective in vitro toxicity of actively proliferating and transformed T-cells. Compared to uninfected Jurkat cells, EPZ015666-treatment also led to a dose-dependent increase in apoptosis in HTLV-1-transformed and ATL-derived cell lines. Using a co-culture model of infection and immortalization, we identified that EPZ015666 is capable of preventing HTLV-1-mediated T-cell immortalization, indicating that PRMT5 is necessary for the transformation process of HTLV-1 in vitro. To determine the importance of PRMT5 activity in vivo, EPZ015666 was administered to NSG xenograft and HTLV-1-infected humanized immune system (HIS) mice, resulting in significantly decreased tumor burden and improved survival outcomes, respectively. Altogether, these findings illustrate that the epigenetic regulator PRMT5 is essential for the survival, transformation, and pathogenesis of HTLV-1, demonstrating the potential utility of this cellular enzyme as a therapeutic target for the treatment of ATL.
References:
1. Panfil, A. R., Al-Saleem, J., Howard, C. M., Mates, J. M., Kwiek, J. J., Baiocchi, R. A., & Green, P. L. (2015). PRMT5 Is Upregulated in HTLV-1-Mediated T-Cell Transformation and Selective Inhibition Alters Viral Gene Expression and Infected Cell Survival. Viruses, 8(1), 7. https://doi.org/10.3390/v8010007
2. Ernzen, K., Melvin, C., Yu, L., Phelps, C., Niewiesk, S., Green, P. L., & Panfil, A. R. (2023). The PRMT5 inhibitor EPZ015666 is effective against HTLV-1-transformed T-cell lines in vitro and in vivo. Frontiers in microbiology, 14, 1101544. https://doi.org/10.3389/fmicb.2023.1101544
Keywords: HTLV-1, ATL, PRMT5