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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1742-1748. Prepublished online as a Blood First Edition Paper on May 24, 2005; DOI 10.1182/blood-2005-02-0695. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-02-0695v1 106/5/1742    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kater, A. P. Articles by Kipps, T. J. Search for Related Content PubMed PubMed Citation Articles by Kater, A. P. Articles by Kipps, T. J. Related Collections Immunobiology Neoplasia Apoptosis Immunotherapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Inhibitors of XIAP sensitize CD40-activated chronic lymphocytic leukemia cells to CD95-mediated apoptosis Arnon P. Kater, Frank Dicker, Massimo Mangiola, Kate Welsh, Richard Houghten, John Ostresh, Adel Nefzi, John C. Reed, Clemencia Pinilla, and Thomas J. Kipps From the Moores Cancer Center, University of California San Diego, La Jolla, CA; the Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Burnham Institute, La Jolla, CA; Torrey Pines Institute for Molecular Sciences, San Diego, CA; and the Chronic Lymphocytic Leukemia Research Consortium, San Diego, CA. Patients with chronic lymphocytic leukemia (CLL) treated with adenovirus CD154 (Ad-CD154, CD40 ligand [CD40L]) gene therapy experienced rapid reductions in leukemia cell counts and lymph node size associated with the induced expression of Fas (CD95). However, CLL cells initially resist CD95-mediated apoptosis within the first 3 days after CD40 ligation in vitro. Thereafter, they become sensitive, which is associated with the CD40-induced expression of the proapoptotic protein B-cell leukemia 2 homology 3 (BH3) interacting domain death agonist (Bid). We hypothesized that the initial resistance to CD95-mediated apoptosis may be due to the high-level expression of X-linked inhibitor of apoptosis protein (XIAP) by CLL cells. Consistent with this, CLL cells from patients 1 day after treatment with autologous Ad-CD154-transduced CLL cells became sensitive to CD95-mediated apoptosis following treatment with a novel XIAP inhibitor, 1540-14. Similarly, 1540-14 specifically enhanced CD95-mediated apoptosis of CLL cells following CD40 ligation in vitro. Immunoblot analyses demonstrated that treatment with 1540-14 allowed CD40-stimulated CLL cells to experience high-level activation of caspases-8 and -3 and cleavage of poly(adenosine diphosphate [ADP]-ribose) polymerase following CD95 ligation. This study demonstrates that distal apoptosis regulators contribute to the initial resistance of CD40-activated CLL cells to CD95-mediated apoptosis and suggests that XIAP inhibitors might enhance the effectiveness of immune-based treatment strategies that target CD40, such as CD154 gene therapy. (Blood. 2005;106:1742-1748) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Old and new drugs join forces against hematologic malignancies Fabio Malavasi Blood 2005 106: 1513-1514. [Full Text] [PDF] This article has been cited by other articles: S. A. G. M. Cillessen, J. C. Reed, K. Welsh, C. Pinilla, R. Houghten, E. Hooijberg, J. Deurhof, K. C. M. Castricum, P. Kortman, C. J. Hess, et al. Small-molecule XIAP antagonist restores caspase-9 mediated apoptosis in XIAP-positive diffuse large B-cell lymphoma cells Blood, January 1, 2008; 111(1): 369 - 375. [Abstract] [Full Text] [PDF] A. P. Kater, M. H. J. van Oers, and T. J. Kipps Cellular immune therapy for chronic lymphocytic leukemia Blood, October 15, 2007; 110(8): 2811 - 2818. [Abstract] [Full Text] [PDF] S. Willimott, M. Baou, S. Huf, S. Deaglio, and S. D. Wagner Regulation of CD38 in proliferating chronic lymphocytic leukemia cells stimulated with CD154 and interleukin-4 Haematologica, October 1, 2007; 92(10): 1359 - 1366. [Abstract] [Full Text] [PDF] C. A. Karikari, I. Roy, E. Tryggestad, G. Feldmann, C. Pinilla, K. Welsh, J. C. Reed, E. P. Armour, J. Wong, J. Herman, et al. Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein Mol. Cancer Ther., March 1, 2007; 6(3): 957 - 966. [Abstract] [Full Text] [PDF] F. Dicker, A. P. Kater, C. E. Prada, T. Fukuda, J. E. Castro, G. Sun, J. Y. Wang, and T. J. Kipps CD154 induces p73 to overcome the resistance to apoptosis of chronic lymphocytic leukemia cells lacking functional p53 Blood, November 15, 2006; 108(10): 3450 - 3457. [Abstract] [Full Text] [PDF] H. Kashkar, J.-M. Seeger, A. Hombach, A. Deggerich, B. Yazdanpanah, O. Utermohlen, G. Heimlich, H. Abken, and M. Kronke XIAP targeting sensitizes Hodgkin lymphoma cells for cytolytic T-cell attack Blood, November 15, 2006; 108(10): 3434 - 3440. [Abstract] [Full Text] [PDF] H. H. Cheung, E. C. LaCasse, and R. G. Korneluk X-linked inhibitor of apoptosis antagonism: strategies in cancer treatment. Clin. Cancer Res., June 1, 2006; 12(11): 3238 - 3242. [Full Text] [PDF]

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