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Loss of FAM46C Promotes Cell Survival in Myeloma

Yuan Xiao Zhu1, Chang-Xin Shi1, Laura A Bruins1

  • 1Division of Hematology, Mayo Clinic Scottsdale, Arizona.

Cancer Research
|June 17, 2017
PubMed

Insights

Wild-type FAM46C protein induces multiple myeloma cell death, while mutations confer survival advantages. FAM46C impacts plasma cell differentiation and endoplasmic reticulum homeostasis, contributing to multiple myeloma progression.

Area of Science:

  • Hematology
  • Cancer Biology
  • Molecular Oncology

Background:

  • The gene FAM46C is frequently mutated in multiple myeloma.
  • The function of FAM46C in multiple myeloma pathogenesis remains unclear.

Purpose of the Study:

  • To investigate the role of wild-type (WT) FAM46C and its mutations in multiple myeloma (MM) pathogenesis.
  • To elucidate the mechanisms by which FAM46C influences MM cell growth, survival, and drug resistance.

Main Methods:

  • Overexpression of WT FAM46C and mutant FAM46C in MM cells.
  • CRISPR-mediated depletion of endogenous FAM46C.
  • Gene expression analysis (RNA sequencing).
  • Pathway analysis (unfolded protein response, mitochondrial dysfunction, signaling pathways).

Main Results:

  • WT FAM46C overexpression caused significant cytotoxicity in MM cells by downregulating IRF4, CEBPB, and MYC, while upregulating immunoglobulin light chain and HSPA5/BIP.
  • FAM46C mutations abrogated cytotoxicity, conferring a survival advantage.
  • FAM46C depletion enhanced MM cell growth, decreased Ig light chain and HSPA5/BIP, activated ERK and antiapoptotic signaling, and conferred resistance to dexamethasone and lenalidomide.
  • Enforced FAM46C expression activated the unfolded protein response and induced mitochondrial dysfunction.
  • Genes altered upon FAM46C depletion were enriched in pathways regulating estrogen, glucocorticoid, B-cell receptor, and ATM signaling.

Conclusions:

  • FAM46C plays a critical role in regulating multiple myeloma cell growth and survival.
  • FAM46C mutations contribute to myeloma pathogenesis and progression by disrupting plasma cell differentiation and endoplasmic reticulum homeostasis.
  • FAM46C is a potential therapeutic target for multiple myeloma.

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