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

Chungyee Leung-Hagesteijn, Natalie Erdmann, Grace Cheung, Jonathan J. Keats, Alexander Keith Stewart, Donna E. Reece, Kim Chan Chung, Rodger E. Tiedemann

Research output: Contribution to journalArticle

188 Citations (Scopus)

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 Bcells 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.

Original languageEnglish (US)
Pages (from-to)289-304
Number of pages16
JournalCancer Cell
Volume24
Issue number3
DOIs
StatePublished - Sep 9 2013

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Proteasome Inhibitors
B-Lymphoid Precursor Cells
Multiple Myeloma
Neoplasms
Plasma Cells
Endoplasmic Reticulum-Associated Degradation
Therapeutics
Endoplasmic Reticulum
Immunoglobulins

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Xbp1s-Negative Tumor B Cells and Pre-Plasmablasts Mediate Therapeutic Proteasome Inhibitor Resistance in Multiple Myeloma. / Leung-Hagesteijn, Chungyee; Erdmann, Natalie; Cheung, Grace; Keats, Jonathan J.; Stewart, Alexander Keith; Reece, Donna E.; Chung, Kim Chan; Tiedemann, Rodger E.

In: Cancer Cell, Vol. 24, No. 3, 09.09.2013, p. 289-304.

Research output: Contribution to journalArticle

Leung-Hagesteijn, C, Erdmann, N, Cheung, G, Keats, JJ, Stewart, AK, Reece, DE, Chung, KC & Tiedemann, RE 2013, 'Xbp1s-Negative Tumor B Cells and Pre-Plasmablasts Mediate Therapeutic Proteasome Inhibitor Resistance in Multiple Myeloma', Cancer Cell, vol. 24, no. 3, pp. 289-304. https://doi.org/10.1016/j.ccr.2013.08.009
Leung-Hagesteijn, Chungyee ; Erdmann, Natalie ; Cheung, Grace ; Keats, Jonathan J. ; Stewart, Alexander Keith ; Reece, Donna E. ; Chung, Kim Chan ; Tiedemann, Rodger E. / Xbp1s-Negative Tumor B Cells and Pre-Plasmablasts Mediate Therapeutic Proteasome Inhibitor Resistance in Multiple Myeloma. In: Cancer Cell. 2013 ; Vol. 24, No. 3. pp. 289-304.
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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 Bcells 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.",
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