FAM46C 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) FAM46C overexpression induces substantial cytotoxicity in multiple myeloma cells.
In contrast, FAM46C mutations found in multiple myeloma 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 pathway and induced mitochondrial
dysfunction. CRISPR-mediated depletion of endogenous FAM46C 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 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.
Cancer Res; 77(16); 4317-27. ©2017 AACR.