Non-Hodgkin lymphoma (NHL) is a heterogeneous group of
blood cancers arising in lymphoid tissues that commonly effects both humans and dogs.
Protein arginine methyltransferase 5 (PRMT5), an
enzyme that catalyzes the symmetric di-methylation of
arginine residues, is frequently overexpressed and dysregulated in both human solid and
hematologic malignancies. In human
lymphoma, PRMT5 is a known driver of malignant transformation and
oncogenesis, however, the expression and role of PRMT5 in canine
lymphoma has not been explored. To explore canine
lymphoma as a useful comparison to human
lymphoma while validating PRMT5 as a rational therapeutic target in both, we characterized expression patterns of PRMT5 in canine
lymphoma tissue microarrays, primary lymphoid biopsies, and canine
lymphoma-derived cell lines. The inhibition of PRMT5 led to growth suppression and induction of apoptosis, while selectively decreasing global marks of
symmetric dimethylarginine (SDMA) and
histone H4 arginine 3 symmetric dimethylation. We performed ATAC-sequencing and gene expression microarrays with pathway enrichment analysis to characterize genome-wide changes in
chromatin accessibility and whole-transcriptome changes in canine
lymphoma cells lines upon PRMT5 inhibition. This work validates PRMT5 as a promising therapeutic target for canine
lymphoma and supports the continued use of the spontaneously occurring canine
lymphoma model for the preclinical development of PRMT5 inhibitors for the treatment of human NHL.