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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 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 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 Mateo, V. Articles by Sarfati, M. Search for Related Content PubMed PubMed Citation Articles by Mateo, V. Articles by Sarfati, M. Related Collections Apoptosis Immunobiology Phagocytes Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 October 2002, Vol. 100, No. 8, pp. 2882-2890 IMMUNOBIOLOGY Mechanisms of CD47-induced caspase-independent cell death in normal and leukemic cells: link between phosphatidylserine exposure and cytoskeleton organization Véronique Mateo, Eric J. Brown, Guy Biron, Manuel Rubio, Alain Fischer, Françoise Le Deist, and Marika Sarfati From the Centre de Recherche du Centre Hospitalier Université Montreal, Laboratoire d' Immunorégulation, Université de Montréal, Canada; Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco; Institut Pasteur, Paris, France; and Institut National Sante et Recherches Médicales U429, Hôpital Necker, Paris, France. 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 (iDCs) phagocytosed the CD47 mAb-killed leukemic cells in the absence of caspases 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, iDCs and CD34+ progenitors were resistant. Structure-function studies in cell lines transfected with various CD47 chimeras demonstrated that killing exclusively required the extracellular and transmembrane 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 phosphatidylserine exposure. Interestingly, CD47 ligation failed to induce cell death in mononuclear cells isolated from Wiskott-Aldrich syndrome (WAS) patients, suggesting the involvement of Cdc42/WAS protein (WASP) signaling pathway. We propose that CD47-induced caspase-independent cell death be mediated by cytoskeleton 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. © 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: S. Bouguermouh, V. Q. Van, J. Martel, P. Gautier, M. Rubio, and M. 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