Loss of <i>FAM46C</i> Promotes Cell Survival in Myeloma

Abstract

<i>FAM46C</i> is one of the most recurrently mutated genes in multiple myeloma; however its role in disease pathogenesis has not been determined. Here we demonstrate that wild-type (WT) <i>FAM46C</i> overexpression induces substantial cytotoxicity in multiple myeloma cells. In contrast, <i>FAM46C</i> mutations found in multiple myeloma patients abrogate this cytotoxicity, indicating a survival advantage conferred by the <i>FAM46C</i> mutant phenotype. WT FAM46C overexpression downregulated <i>IRF4, CEBPB</i>, and <i>MYC</i> and upregulated immunoglobulin (Ig) light chain and <i>HSPA5</i>/<i>BIP</i> Furthermore, pathway analysis suggests that enforced <i>FAM46C</i> expression activated the unfolded protein response pathway and induced mitochondrial dysfunction. CRISPR-mediated depletion of endogenous <i>FAM46C</i> enhanced multiple myeloma cell growth, decreased Ig light chain and HSPA5/BIP expression, activated ERK and antiapoptotic signaling, and conferred relative resistance to dexamethasone and lenalidomide treatments. Genes altered in <i>FAM46C</i>-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 <i>FAM46C</i> mutation as a contributor to myeloma pathogenesis and disease progression via perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis. <i>Cancer Res; 77(16); 4317-27. ©2017 AACR</i>.