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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. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-10-116848v1 113/3/626    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Leleu, X. Articles by Treon, S. P. Search for Related Content PubMed PubMed Citation Articles by Leleu, X. Articles by Treon, S. P. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Endoplasmic reticulum stress is a target for therapy in Waldenstrom macroglobulinemia Xavier Leleu1,2,*, Lian Xu1,*, Xiaoying Jia3, Antonio Sacco3, Mena Farag3, Zachary R. Hunter1, Anne-Sophie Moreau2, Hai T. Ngo3, Evdoxia Hatjiharissi1, Allen W. Ho1, Daniel D. Santos1, Sofia Adamia1, Kelly O'Connor1, Bryan Ciccarelli1, Jacob Soumerai1, Robert J. Manning1, Christopher J. Patterson1, Aldo M. Roccaro3, Irene M. Ghobrial3, and Steven P. Treon1 1 Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; 2 Service des maladies du sang et Laboratoire d'Immunologie, Centre Hospitalier Régional Universitaire (CHRU), Lille, France; and 3 Kirsch Laboratory for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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