Loss of FAM46C promotes cell survival in myeloma

FAM46C is one of the most recurrently mutated genes in multiple myeloma (MM), however its role in disease pathogenesis has not been determined. Here we demonstrate that wild type (WT) FAM46C overexpression induces substantial cytotoxicity in MM cells. In contrast, FAM46C mutations found in MM patients abrogate this cytotoxicity, indicating a survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, and MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP. Furthermore, pathway analysis suggests that enforced FAM46C expression activated the unfolded protein response (UPR) pathway and induced mitochondrial dysfunction. CRISPR-mediated depletion of endogenous FAM46C enhanced MM cell growth, decreased Ig light chain and BIP expression, activated ERK and anti-apoptotic signaling, and conferred relative resistance to dexamethasone and lenalidomide treatments. Genes altered in FAM46C-depleted cells were enriched for signaling pathways regulating estrogen, glucocorticoid, B cell receptor signaling, and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival and identify FAM46C mutation as a contributor to myeloma pathogenesis and disease progression via perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis.

http://ift.tt/2syz1m5