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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2001-12-0327. This Article Full Text (PDF) All Versions of this Article: 2001-12-0327v1 100/5/1810    most recent Alert me when this article is cited Alert me if a correction is posted 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 Bellosillo, B. Articles by Colomer, D. Search for Related Content PubMed PubMed Citation Articles by Bellosillo, B. Articles by Colomer, D. Social Bookmarking                   What's this? Submitted December 27, 2001 Accepted April 23, 2002 Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic lymphocytic leukemia Beatriz Bellosillo, Neus Villamor, Armando Lopez-Guillermo, Silvia Marce, Francesc Bosch, Elias Campo, Emili Montserrat*, and Dolors Colomer Hematopathology Unit, Hospital Clinic.IDIBAPS, Barcelona, Spain Department of Hematology, Hospital Clinic.IDIBAPS. University of Barcelona, Barcelona, Spain Department of Pathology, Hospital Clinic.IDIBAPS. University of Barcelona, Barcelona, Spain * Corresponding author; email: emontse{at}clinic.ub.es. The role of Bax and Bak, two proapoptotic proteins of the Bcl-2 family, was analyzed in primary B-cell chronic lymphocytic leukemia (CLL) cells following in vitro treatment with fludarabine, dexamethasone or the combination of fludarabine with cyclophosphamide and mitoxantrone (FCM). A strong correlation was found between the number of apoptotic cells and the percentage of cells stained with antibodies recognizing conformational changes of Bax (n=33, r=0.836, p<0.001) or Bak (n=10, r=0.948, p<0.001). Preincubation of CLL cells with Z-VAD.fmk, a broad caspase inhibitor, abolished caspase-3 activation, exposure of phosphatidylserine residues, and ROS generation, partially reverted the loss of transmembrane mitochondrial potential (m), but did not affect Bax or Bak conformational changes. These results indicate that the translocation of Bax and Bak occurs upstream of caspase activation or is caspase-independent. Following drug-induced apoptosis, Bax integrates into mitochondria, as demonstrated by fluorescence microscopy and Western blot, without changes in the total amount of Bax or Bak protein. Fludarabine and FCM induce p53 stabilization, but it does not seem to be essential in inducing Bax and Bak conformational changes, as these are also observed in dexamethasone-treated CLL cells. These results demonstrate that, in CLL cells, the change in the intracellular localization of Bax from cytosol to mitochondria, and the conformational changes of Bax and Bak are one of the early steps in the induction of cell death. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Lopez-Guerra, G. Roue, P. Perez-Galan, R. Alonso, N. Villamor, E. Montserrat, E. Campo, and D. Colomer p65 Activity and ZAP-70 Status Predict the Sensitivity of Chronic Lymphocytic Leukemia Cells to the Selective I{kappa}B Kinase Inhibitor BMS-345541 Clin. Cancer Res., April 15, 2009; 15(8): 2767 - 2776. [Abstract] [Full Text] [PDF] M. Lopez-Guerra, L. Trigueros-Motos, M. Molina-Arcas, N. Villamor, F. J. Casado, E. Montserrat, E. 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