Objective:
MM still remains an incurable B-cell malignancy and subsets of patients have high-risk features linked with dismal outcome. Therefore, the need for additional therapeutic options remains. In recent years, epigenetic and DNA repair pathway alterations were identified. We performed a pre-clinical evaluation of Protein Arginine Methyltransferase 5 (PRMT5) inhibition, important in epigenetic regulation of tumor suppressor genes and protein methylation, as a novel treatment strategy in high-risk multiple myeloma (MM) patients.
Methods:
We identified PRMT5 as a potential prognostic and therapeutic target using publically available gene-expression data of MM patients, including the CoMMpass study. Druggability was evaluated in OPM2, JJN3 and XG7 human myeloma cell lines using the PRMT5-inhibitor EPZ015938. Apoptosis and cell cycle assays were performed using AnnexinV/7AAD- and PI-staining, respectively. Effects on gene transcription and protein expression was evaluated with RNA-sequencing and western blot.
Results:
Decreased progression-free survival was seen in CoMMpass study patients with high PRMT5-expression (112.7 vs 189.9 weeks, p=0.003). PRMT5-inhibition in MM cell lines resulted in decreased cell growth and increased AnnexinV-positivity. XG-7 cells appeared more sensitive compared to JJN3 and OPM2 cells. Cell cycle analysis revealed a significant increase in cells in G2/M phase in JJN3 and OPM2 cells, as well as a decrease in S-phase in OPM2 cells. No major difference upon treatment in XG-7 cells were observed besides an increase in subG1 cells. RNAseq revealed an important role for PRMT5 in regulating alternative splicing, nonsense-mediated decay, DNA repair and PI3K/mTOR-signaling, irrespective of cell line type.
 
Conclusion:
We have identified that PRMT5 is important for MM cell growth and survival. Analysis of the transcriptome after PRMT5 inhibition reveals the importance of alternative splicing and PI3K/mTOR signalling, providing evidence that these pathways are implicated in high-risk MM disease. The role of PRMT5 in MM pathogenesis and treatment strategies thus warrants further investigation.

Targeting Protein Arginine Methyltransferase PRMT5 in High-risk Multiple Myeloma: A New Treatment Strategy?