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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.
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Submitted February 18, 2005
Accepted May 9, 2005
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*
Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA; Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Chronic Lymphocytic Leukemia Research Consortium, La Jolla, CA, USA
Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA; Chronic Lymphocytic Leukemia Research Consortium, La Jolla, CA, USA
Burnham Institute, La Jolla, CA, USA; Chronic Lymphocytic Leukemia Research Consortium, La Jolla, CA, USA
Burnham Institute, La Jolla, CA, USA
Torrey Pines Institute for Molecular Sciences, San Diego, CA, USA
* Corresponding author; email: tkipps{at}ucsd.edu.
Chronic lymphocytic leukemia (CLL) patients treated with adenovirus (Ad)-CD154 (CD40L) gene therapy experienced rapid reductions in leukemia-cell counts and lymph-node size associated with the induced expression 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 pro-apoptotic protein BH3 interacting domain death agonist (Bid). We hypothesized 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 one 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(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.

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