Endoplasmic reticulum stress is a target for therapy in Waldenstrom macroglobulinemia
Open Access
- 15 January 2009
- journal article
- Published by American Society of Hematology in Blood
- Vol. 113 (3), 626-634
- https://doi.org/10.1182/blood-2007-10-116848
Abstract
Waldenstrom macroglobulinemia (WM) is an incurable low-grade lymphoma characterized by bone marrow (BM) involvement of IgM secreting lymphoplasmacytic cells. The induction of unfolded protein response (UPR) genes (“physiologic” UPR) enables cells to differentiate into professional secretory cells capable of production of high amounts of endoplasmic reticulum (ER)–processed proteins, such as immunoglobulins. Ultimately, the initially cytoprotective UPR triggers an apoptotic cascade if ER stress is not corrected, called proapoptotic/terminal UPR. We show that WM cells inherently express the physiologic UPR machinery compared with normal BM cells, and that increased ER stress leads to proapoptotic/terminal UPR in WM cells. We therefore examined tunicamycin, ER stress inducer, for potential antitumor effects in WM. Tunicamycin induced significant cytotoxicity, apoptosis and cell-cycle arrest, and inhibited DNA synthesis in WM cell lines and primary BM CD19+ cells from patients with WM with an inhibitory concentration (IC50) of 0.5 μg/mL to 1 μg/mL, but not in healthy donor cells. Importantly, coculture of WM cells in the context of the BM microenvironment did not inhibit tunicamycin-induced cytotoxicity. Finally, we demonstrate that ER stress inducer synergizes with other agents used in the treatment of WM. These preclinical studies provide a framework for further evaluation of ER stress inducing agents as therapeutic agents in WM.This publication has 43 references indexed in Scilit:
- Combination Mammalian Target of Rapamycin Inhibitor Rapamycin and HSP90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin Has Synergistic Activity in Multiple MyelomaClinical Cancer Research, 2006
- Adaptation to ER Stress Is Mediated by Differential Stabilities of Pro-Survival and Pro-Apoptotic mRNAs and ProteinsPLoS Biology, 2006
- Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cellsBlood, 2006
- From acute ER stress to physiological roles of the Unfolded Protein ResponseCell Death & Differentiation, 2006
- Protein Folding in the Endoplasmic Reticulum and the Unfolded Protein ResponsePublished by Springer Science and Business Media LLC ,2006
- Antimyeloma activity of heat shock protein-90 inhibition.Blood, 2005
- Quantitative measurement of events in the mammalian unfolded protein responseMethods, 2005
- ER stress and the unfolded protein responseMutation Research - Reviews in Mutation Research, 2005
- Sequential Waves of Functionally Related Proteins Are Expressed When B Cells Prepare for Antibody SecretionImmunity, 2003
- Activation of an Unfolded Protein Response during Differentiation of Antibody-secreting B CellsOnline Journal of Public Health Informatics, 2002