CANCER CELL:: Proteasome inhibitor mechanism in MM.

Cancer Cell, Volume 24, Issue 3, 289-304, 9 September 2013 Copyright © 2013 Elsevier Inc. All rights reserved. 10.1016/j.ccr.2013.08.009 Authors Chungyee Leung-Hagesteijn, Natalie Erdmann, Grace Cheung, Jonathan J. Keats, A. Keith Stewart, Donna E. Reece, Kim Chan Chung, Rodger E. Tiedemann Highlights 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 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.