Abstract
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.
Highlights
Lymphoma is one of the most common malignant cancers in dogs, accounting for 7–24% of all cancers and 83% of hematopoietic malignancies
Given the relevance of Protein arginine methyltransferase 5 (PRMT5) to lymphomagenesis in humans, we hypothesized that PRMT5 would be overexpressed in canine lymphomas
To elucidate the mechanism of PRMT5 inhibitor-mediated cell death in canine lymphoma, we performed a separate gene set overlap analysis between the 290 down-regulated differentially expressed genes (DEGs) after PRMT5 inhibition and Molecular Signatures Database (MSigDB) Oncogenic Signatures (Fig 5D). This analysis overlapped significantly with gene expression changes after knock down of EED, genes up-regulated in cells overexpressing MYC, genes up-regulated after knock down of SNF5, and genes up-regulated after RB1 knock down. These results suggest that inhibition of PRMT5 in canine lymphoma can attenuate oncogenic MYC signaling while reactivating the RB tumor suppressor pathway and PRC2 silencing, an established mechanism of human lymphoma cell death after PRMT5 inhibition [37]
Summary
Lymphoma is one of the most common malignant cancers in dogs, accounting for 7–24% of all cancers and 83% of hematopoietic malignancies. The majority of lymphomas in dogs are histopathologically high-grade and of B-cell origin. The current most effective treatment for intermediate/high-grade lymphoma in dogs is multi-agent cytotoxic chemotherapy, with the best remission and survival times being reported with doxorubicin-based sequential chemotherapy protocols similar to CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) [9,10]. Even using such multi-agent cytotoxic chemotherapy protocols, the median survival time for affected dogs is only about one year, with an approximate 20% two year survival [10]
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