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Blood, 15 January 2009, Vol. 113, No. 3, pp. 626-634.
Prepublished online as a Blood First Edition Paper on November 3, 2008; DOI 10.1182/blood-2007-10-116848.
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Submitted October 5, 2007
Accepted September 9, 2008
Endoplasmic reticulum stress is a target for therapy in Waldenstrom macroglobulinemia
Xavier Leleu, Lian Xu, Xiaoying Jia, Antonio Sacco, Mena Farag, Zachary R Hunter, Anne-Sophie Moreau, Hai T Ngo, Evdoxia Hatjiharissi, Allen W Ho, Daniel D Santos, Sofia Adamia, Kelly O'Connor, Bryan Ciccarelli, Jacob Soumerai, Robert J Manning, Christopher J. Patterson, Aldo M Roccaro, Irene M Ghobrial, and Steven P Treon*
Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States
Service des maladies du sang et Laboratoire d'Immunologie, CHRU, Lille, France
* Corresponding author; email: steven_treon{at}dfci.harvard.edu.
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 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 physiological UPR machinery compared to 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 anti-tumor 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 WM patients with an IC50 of 0.5 to 1µg/mL, but not in healthy donor cells. Importantly, co-culture 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 pre-clinical studies provide a framework for further evaluation of ER stress inducing agents as therapeutic agents in WM.
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