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

C Leung-Hagesteijn, N Erdmann, G Cheung, JJ Keats… - Cancer cell, 2013 - cell.com
C Leung-Hagesteijn, N Erdmann, G Cheung, JJ Keats, AK Stewart, DE Reece, KC Chung…
Cancer cell, 2013cell.com
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 …
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.
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