Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma

Cancer Cell. 2013 Sep 9;24(3):289-304. doi: 10.1016/j.ccr.2013.08.009.

Abstract

Proteasome inhibitor (PI) resistance mechanisms in multiple myeloma (MM) remain controversial. We report the existence of a progenitor organization in primary MM that recapitulates maturation stages between B cells and plasma cells and that contributes to clinical PI resistance. Xbp1s(-) tumor B cells and pre-plasmablasts survive therapeutic PI, preventing cure, while maturation arrest of MM before the plasmablast stage enables progressive disease on PI treatment. Mechanistically, suppression of Xbp1s in MM is shown to induce bortezomib resistance via de-commitment to plasma cell maturation and immunoglobulin production, diminishing endoplasmic reticulum (ER) front-loading and cytotoxic susceptibility to PI-induced inhibition of ER-associated degradation. These results reveal the tumor progenitor structure in MM and highlight its role in therapeutic failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / metabolism
  • Boronic Acids / pharmacology
  • Boronic Acids / therapeutic use
  • Bortezomib
  • Cell Survival / drug effects
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Neoplasm / genetics*
  • Endoplasmic Reticulum Stress
  • Endoribonucleases / metabolism
  • Humans
  • Immunophenotyping
  • Membrane Proteins / metabolism
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / metabolism
  • Mutation
  • Plasma Cells / metabolism
  • Plasma Cells / pathology
  • Precursor Cells, B-Lymphoid / metabolism
  • Precursor Cells, B-Lymphoid / pathology
  • Proteasome Inhibitors / pharmacology
  • Proteasome Inhibitors / therapeutic use*
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyrazines / pharmacology
  • Pyrazines / therapeutic use
  • Regulatory Factor X Transcription Factors
  • Signal Transduction
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • X-Box Binding Protein 1
  • eIF-2 Kinase / metabolism

Substances

  • Activating Transcription Factor 6
  • Boronic Acids
  • DNA-Binding Proteins
  • Membrane Proteins
  • Proteasome Inhibitors
  • Pyrazines
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Bortezomib
  • ERN2 protein, human
  • PERK kinase
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase
  • Endoribonucleases

Associated data

  • GEO/GSE44968