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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2718-2726. Prepublished online as a Blood First Edition Paper on October 2, 2003; DOI 10.1182/blood-2003-04-1317. This Article Full Text (PDF) All Versions of this Article: 2003-04-1317v1 103/7/2718    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 Decker, T. Articles by Licht, T. Search for Related Content PubMed PubMed Citation Articles by Decker, T. Articles by Licht, T. Social Bookmarking                   What's this? Submitted April 29, 2003 Accepted September 8, 2003 Induction of Caspase-Dependent Programmed Cell Death in B-Cell Chronic Lymphocytic Leukemia Cells by Anti-CD22 Immunotoxins Thomas Decker*, Madlene Oelsner, Robert J Kreitman, Giuliana Salvatore, Qing-cheng Wang, Ira Pastan, Christian Peschel, and Thomas Licht III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitaet Munchen, Munich, Germany Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Istituto di Endocrinologia ed Oncologia Sperimentale del C.N.R., Dipartimento di Biologia e Patologia Cellulare e Molecolare, Medical School, University 'Federico II', Napoli, Italy * Corresponding author; email: t.decker{at}lrz.tu-muenchen.de. B-CLL cells are long-lived in vivo, possibly due to defects in apoptosis. We investigated BL22, an immunotoxin composed of the Fv-portion of an anti-CD22 antibody fused to a 38kDa Pseudomonas exotoxin-A fragment. B-cells from 22 CLL patients were immunomagnetically enriched (96% purity), and cultured with BL22 or an immunotoxin that does not recognize hematopoietic cells. The antileukemic activity of BL22 was correlated with CD22 expression as determined by flow cytometry. BL22 induced caspase-9 and caspase-3 activation, poly(ADP-ribose)polymerase (PARP) cleavage, DNA fragmentation and membrane flipping. Cell death was associated with loss of mitochondrial membrane potential and down-regulation of Mcl-1 and XIAP. Furthermore, BL22 induced a proapoptotic 18kDa Bax protein and conformational changes of Bax. Z-VAD.fmk abrogated apoptosis, confirming that cell death was executed by caspases. Conversely, interleukin-4, a survival factor, inhibited spontaneous death in culture, but failed to prevent from immunotoxin-induced apoptosis. BL22 cytotoxicity was markedly enhanced when combined with anticancer drugs including vincristine. We also investigated HA22, a newly engineered immunotoxin, in which BL22 residues are mutated to improve target binding. HA22 was much more active than BL22. In conclusion, these immunotoxins induce caspase-mediated apoptosis involving mitochondrial damage. Combination with chemotherapy is expected to improve the efficacy of immunotoxin treatment. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. Kojima, M. Konopleva, T. McQueen, S. O'Brien, W. Plunkett, and M. Andreeff Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia Blood, August 1, 2006; 108(3): 993 - 1000. [Abstract] [Full Text] [PDF] T. E. Battle, J. Arbiser, and D. A. Frank The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells Blood, July 15, 2005; 106(2): 690 - 697. [Abstract] [Full Text] [PDF]

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