Xbp1s-Negative Tumor B Cells and Pre-Plasmablasts Mediate Therapeutic Proteasome Inhibitor Resistance in Multiple Myeloma

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...

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Bibliographic Details
Published in:Cancer cell 2013-09, Vol.24 (3), p.289-304
Main Authors: Leung-Hagesteijn, Chungyee, Erdmann, Natalie, Cheung, Grace, Keats, Jonathan J., Stewart, A. Keith, Reece, Donna E., Chung, Kim Chan, Tiedemann, Rodger E.
Format: Article
Language:English
Subjects:
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
eIF-2 Kinase - metabolism
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
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Summary: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. •MM tumors contain Xbp1s− progenitors that survive proteasome inhibition•Xbp1s absence arrests secretory maturation and ER loading, reducing ERAD dependence•PI resistance mechanisms in patients differ from in vitro models•These data help explain the failure to cure MM with current therapy
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2013.08.009