Loss of FAM46C promotes cell survival in myeloma

Yuan Xiao Zhu, Chang Xin Shi, Laura A. Bruins, Patrick Jedlowski, Xuewei Wang, K. Martin Kortüm, Moulun Luo, Jonathan M. Ahmann, Esteban Braggio, A. Keith Stewart

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4317-4327
Number of pages11
JournalCancer research
Volume77
Issue number16
DOIs
StatePublished - Aug 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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