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Prepublished online as a Blood First Edition Paper on June 14, 2002; DOI 10.1182/blood-2001-12-0217. This Article Full Text (PDF) All Versions of this Article: 2001-12-0217v1 100/8/2882    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 Mateo, V. Articles by Sarfati, M. Search for Related Content PubMed PubMed Citation Articles by Mateo, V. Articles by Sarfati, M. Social Bookmarking                   What's this? Submitted December 14, 2001 Accepted May 23, 2002 Mechanisms of CD47-induced caspase-independent cell death in normal and leukemia cells: link between phosphatidylserine exposure and cytoskeleton organization Veronique Mateo, Eric J Brown, Guy Biron, Manuel Rubio, Alain Fischer, Francoise Le Deist, and Marika Sarfati* Immune Regulation Laboratory, Centre de Recherche CHUM, Montreal, QC, Canada; Immunologie Inflammation, Institut Pasteur, Paris, France Program in Host-Pathogen Interactions, University of California, San Francisco, USA Immune Regulation Laboratory, Centre de Recherche CHUM, Montreal, QC, Canada INSERM U429, Hopital Necker, Paris, France * Corresponding author; email: m.sarfati{at}umontreal.ca. Dying cells, apoptotic or necrotic, are swiftly eliminated by professional phagocytes. We previously reported that CD47 engagement by CD47 mAb or thrombospondin induced caspase-independent cell death of chronic lymphocytic leukemic B cells (B-CLL). Here we show that human immature dendritic cells (DCs) phagocytosed the CD47 mAb-killed leukemic cells in the absence of caspase 3, 7, 8 and 9 activation in the malignant lymphocytes. Yet, the dead cells displayed the cytoplasmic features of apoptosis including cell shrinkage, phosphatidylserine exposure and decreased mitochondrial transmembrane potential (m). CD47 mAb-induced cell death also occurred in normal resting and activated lymphocytes, with B-CLL cells demonstrating the highest susceptibility. Importantly, immature DCs and CD34+ progenitors cells were resistant. Structure-function studies in cell lines transfected with various CD47 chimera demonstrated that killing exclusively required the extracellular and transmenbrane domains of the CD47 molecule. Cytochalasin-D, an inhibitor of actin polymerization and antimycin A, an inhibitor of mitochondrial electron transfer, completely suppressed CD47-induced PS exposure. Interestingly, CD47 ligation failed to induce cell death in mononuclear cells isolated from Wiskott-Aldrich syndrome patients suggesting the involvement of Cdc42/WASP signaling pathway. We propose that CD47-induced caspase-independent cell death is mediated by cytoskeletal reorganization. This form of cell death may be relevant to maintenance of homeostasis and as such might be explored for the development of future therapeutic approaches in lymphoid malignancies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Barbier, L. Chatre, M. Bras, P. Sancho, G. Roue, C. Virely, V. J. Yuste, S. Baudet, M. Rubio, J. E. Esquerda, et al. Caspase-independent type III programmed cell death in chronic lymphocytic leukemia: the key role of the F-actin cytoskeleton Haematologica, April 1, 2009; 94(4): 507 - 517. [Abstract] [Full Text] [PDF] E. Spanoudakis, M. Hu, K. Naresh, E. Terpos, V. Melo, A. Reid, I. 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