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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 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 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 Bellosillo, B. Articles by Colomer, D. Search for Related Content PubMed PubMed Citation Articles by Bellosillo, B. Articles by Colomer, D. Related Collections Apoptosis Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 September 2002, Vol. 100, No. 5, pp. 1810-1816 NEOPLASIA 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 López-Guillermo, Silvia Marcé, Francesc Bosch, Elias Campo, Emili Montserrat, and Dolors Colomer From the Departments of Hematology and Pathology, Institute of Hematology and Oncology from Hospital Clínic, Postgraduate School of Hematology Farreras-Valentí; Institut d'Investigacions Biomèdiques August Pi i Sunyer; and University of Barcelona, Spain. The role of Bax and Bak, 2 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 < .001) or Bak (n = 10; r = 0.948; P < .001). Preincubation of CLL cells with Z-VAD.fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone), a broad caspase inhibitor, abolished caspase-3 activation, exposure of phosphatidylserine residues, and reactive oxygen species generation; partially reversed the loss of transmembrane mitochondrial potential (m); but did not affect Bax or Bak conformational changes. These results indicate that the conformational changes of Bax and Bak occur upstream of caspase activation or are 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 do not seem to be essential in inducing Bax and Bak conformational changes, as they 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 among the early steps in the induction of cell death. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Gine, M. Crespo, A. Muntanola, E. Calpe, M. J. Baptista, N. Villamor, E. 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