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 D Braggio, Alexander Keith Stewart

Research output: Contribution to journalArticle

17 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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    Zhu, Y. X., Shi, C. X., Bruins, L. A., Jedlowski, P., Wang, X., Kortüm, K. M., Luo, M., Ahmann, J. M., Braggio, E. D., & Stewart, A. K. (2017). Loss of FAM46C promotes cell survival in myeloma. Cancer Research, 77(16), 4317-4327. https://doi.org/10.1158/0008-5472.CAN-16-3011