CANCER CELL: Xbp1s-Negative Tumor B Cells and Pre-Plasmablasts mediate Proteasome inhibitor resistance in "Multiple Myeloma.

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 Xbp1s-Negative Tumor B Cells and Pre-Plasmablasts Mediate Therapeutic Proteasome Inhibitor Resistance in Multiple Myeloma Authors Chungyee Leung-Hagesteijn, Natalie Erdmann, Grace Cheung, Jonathan J. Keats, A. Keith Stewart(SCOTTSDALE MAYO CLINIC), Donna E. Reece,(Toronto Princess Marg.Hosp) Kim Chan Chung, Rodger E. Tiedemann (Tor.Princess Marg.Hosp) 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. COMMENT from SCIENCE Cancer Researchers Discover Root Cause of Multiple Myeloma Relapse Sep. 9, 2013 — Clinical researchers at Princess Margaret Cancer Centre ( and SCOTTSDALE MAYO CLINIC) have discovered why multiple myeloma, an incurable cancer of the bone marrow, persistently escapes cure by an initially effective treatment that can keep the disease at bay for up to several years. The reason, explains research published online today in Cancer Cell, is intrinsic resistance found in immature progenitor cells that are the root cause of the disease -- and relapse -- says principal investigator Dr. Rodger Tiedemann, a hematologist specializing in multiple myeloma and lymphoma at the Princess Margaret, University Health Network (UHN). Dr. Tiedemann is also an Assistant Professor in the Faculty of Medicine, University of Toronto. The research demonstrates that the progenitor cells are untouched by mainstay therapy that uses a proteasome inhibitor drug ("Velcade") to kill the plasma cells that make up most of the tumour. The progenitor cells then proliferate and mature to reboot the disease process, even in patients who appeared to be in complete remission. "Our findings reveal a way forward toward a cure for multiple myeloma, which involves targeting both the progenitor cells and the plasma cells at the same time," says Dr. Tiedemann. "Now that we know that progenitor cells persist and lead to relapse after treatment, we can move quickly into clinical trials, measure this residual disease in patients, and attempt to target it with new drugs or with drugs that may already exist. Dr. Tiedemann talks about his findings: click here to watch. In tackling the dilemma of treatment failure, the researchers identified a cancer cell maturation hierarchy within multiple myeloma tumors and demonstrated the critical role of myeloma cell maturation in proteasome inhibitor sensitivity. The implication is clear for current drug research focused on developing new proteasome inhibitors: targeting this route alone will never cure multiple myeloma. Dr. Tiedemann says: "If you think of multiple myeloma as a weed, then proteasome inhibitors such as Velcade are like a persnickety goat that eats the mature foliage above ground, producing a remission, but doesn't eat the roots, so that one day the weed returns." The research team initially analyzed high-throughput screening assays of 7,500 genes in multiple myeloma cells to identify effectors of drug response, and then studied bone marrow biopsies from patients to further understand their results. The process identified two genes (IRE1 and XBP1) that modulate response to the proteasome inhibitor Velcade and the mechanism underlying the drug resistance that is the barrier to cure. Dr. Tiedemann is part of the latest generation of cancer researchers at UHN building on the international legacy of Drs. James Till and the late Ernest McCulloch, who pioneered a new field of science in 1961 with their discovery that some cells ("stem cells") can self-renew repeatedly. The science has continued to advance unabated ever since, and notably with key discoveries by Dr. John Dick of cancer stem cells first in leukemia and next in colon cancer. Dr. Tiedemann's new findings underscore the clinical importance of understanding how cells are organized in the disease process.