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

• Published in: Cancer cell Vol. 24; no. 3; pp. 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: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.09.2013
• 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
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2013.08.009

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