biostudies-literatureZhu YXNCI NIH HHS4317-4327https://www.ebi.ac.uk/biostudies/studies/S-EPMC5586597biostudies-literatureUnknown77(16)<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>.Cancer researchLoss of <i>FAM46C</i> Promotes Cell Survival in Myeloma.PMC5586597R01 CA183968P50 CA186781Ahmann JMStewart AKLuo MZhu YXWang XBraggio EJedlowski PShi CXKortum KMBruins LAfalseLoss of <i>FAM46C</i> Promotes Cell Survival in Myeloma.<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>.2017-01-01T00:00:00Z2017 Aug2024-11-14T12:46:09.106Z2019-03-26T23:51:03ZS-EPMC55865972861970910.1158/0008-5472.can-16-301110.1158/0008-5472.CAN-16-3011