TARGETING PROTEIN ARGININE METHYLTRANFERASE PRMT5 IN HIGH-RISK MULTIPLE MYELOMA: A NEW TREATMENT STRATEGY?

Objective: 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.
Description: MM is 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.
Materials and Methods: We identified PRMT5 using publically available gene-expression data of MM patients. Its prognostic value was validated in the CoMMpass study. Druggability was evaluated in OPM2 and JJN3 cells using PRMT5-inhibitors EPZ015666 and EPZ015938. Apoptosis and cell cycle assays were performed using AnnexinV/7AAD- and PI-staining, respectively. Protein expression was evaluated with 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 OMP2 and JJN3 cells showed decreased cell growth at day 3 and increased AnnexinV positivity was observed starting from 6 days of treatment. Cell cycle analysis revealed no major difference upon treatment in JJN3 cells. For OPM2 an increase in subG1- and G2-phase and decrease in S-phase was seen on day 6. On a protein level, decreased global symmetric arginine di-methylation was seen alongside decreased levels of E2F1, a PRMT5 target involved in the Rb1/E2F cell cycle regulatory pathway.
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.