Validation of protein arginine methyltransferase 5 (PRMT5) as a candidate therapeutic target in the spontaneous canine model of non-Hodgkin lymphoma [array]

Targeting PRMT5 in canine lymphoma: we characterized expression patterns of PRMT5 in canine lymphomas and correlated these with histological subtypes using tissue microarrays. We characterized expression of PRMT5 in three canine lymphoma-derived cell lines and primary lymph node biopsies. We have demonstrated that inhibition of PRMT5 leads to growth suppression and induction of apoptosis in canine lymphoma cell lines and primary canine lymphoma cells in a time and dose-dependent manner, while selectively decreasing global marks of symmetric dimethylarginine (SDMA) and histone H4 arginine 3 symmetric di-methylation. We performed ATAC-sequencing with pathway enrichment analysis to characterize genome-wide changes in chromatin accessibility after PRMT5 inhibition. We performed gene expression microarrays with pathway analysis to characterize whole transcriptome changes in canine lymphoma cell lines treated with PRMT5 inhibitors. This work validates PRMT5 as a promising therapeutic target for canine lymphoma and supports the continued used of the spontaneously occurring canine lymphoma model for the preclinical development of PRMT5 inhibitors for the treatment of human NHL. RNA was isolated from the canine B-cell lymphoma cell lines CLBL-1 and 17-71 after treated with 100 nM of PR220, a selective protein arginine methyltransferase (PRMT5) inhibitor. Whole transcriptome profiling was preformed using Affymetrix microarrays to evaluate changes in gene expression after PRMT5 inhibition.