title: Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma.
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.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Chungyee
authors.initials: C
authors.lastname: Leung-Hagesteijn
authors.forename: Natalie
authors.initials: N
authors.lastname: Erdmann
authors.forename: Grace
authors.initials: G
authors.lastname: Cheung
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Keats
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.forename: Donna E
authors.initials: DE
authors.lastname: Reece
authors.forename: Kim Chan
authors.initials: KC
authors.lastname: Chung
authors.forename: Rodger E
authors.initials: RE
authors.lastname: Tiedemann
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D008565:Membrane Proteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism / Q000473:pathology; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D001897:Boronic Acids; D000069286:Bortezomib; D004268:DNA-Binding Proteins; D004722:Endoribonucleases; D008565:Membrane Proteins; D061988:Proteasome Inhibitors; D017346:Protein Serine-Threonine Kinases; D011719:Pyrazines; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C000605543:XBP1 protein, human; C403982:ERN2 protein, human
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