Protein arginine methyltransferase PRMT5 in high-risk multiple myeloma : A possible new treatment strategy?

Multiple myeloma (MM), even in the age of novel agents, remains an incurable B-cell malignancy. It is known that a certain subset of patients have high-risk features linked with dismal outcome. Therefore, the need for additional therapeutic options remains high. The past years, a role for epigenetic dysregulations and DNA repair pathway alterations have been identified in MM pathogenesis. We analyzed the prognostic significance of different epigenetic and DNA repair target genes using publically available gene-expression data of MM patients. We identified Protein Arginine Methyltransferase 5 (PRMT5), known to play a role in epigenetic regulation of tumor suppressor genes and protein methylation, as a potential target gene in high-risk patients. We validated the clinical and prognostic significance of PRMT5 in the CoMMpass Study, showing a significant decrease in progression-free survivial in patients with high PRMT5 expression (112.7 vs 189.9 weeks, p=0.003). We evaluated the role of PRMT5 as a druggable target in different human myeloma cell lines with the use of a PRMT5 inhibitor, EPZ015666. EPZ015666 treatment of OMP2, U266 and JJN3 cells showed a significant decrease in cell growth over the course of treatment, without striking effects on the cell cycle profile. Increased amount of AnnexinV positivity was observed starting from 6 days of treatment. Furthermore, a combinatory effect on MM cell viability was seen when EPZ015666 was combined with melphalan, an alkylating agent. On a protein level, a decrease of global symmetric arginine di-methylation was seen alongside decreased levels of E2F1, a PRMT5 target involved in the Rb1/E2F cell cycle regulatory pathway. In conclusion, we have identified that PRMT5 is important for MM cell growth and survival. The role of PRMT5 in MM pathogenesis and treatment strategies warrants further investigation.