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Prepublished online as a Blood First Edition Paper on September 5, 2002; DOI 10.1182/blood-2002-06-1774. This Article Full Text (PDF) All Versions of this Article: 2002-06-1774v1 101/3/1080    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 Tehranchi, R. Articles by Hellstrom-Lindberg, E. Search for Related Content PubMed PubMed Citation Articles by Tehranchi, R. Articles by Hellstrom-Lindberg, E. Social Bookmarking                   What's this? Submitted June 14, 2002 Accepted August 27, 2002 Granulocyte colony-stimulating factor inhibits spontaneous cytochrome c release and mitochondria-dependent apoptosis of myelodysplastic syndrome hematopoietic progenitors Ramin Tehranchi, Bengt Fadeel, Ann-Mari Forsblom, Birger Christensson, Jan Samuelsson, Boris Zhivotovsky, and Eva Hellstrom-Lindberg* Department of Medicine, Div of hematology, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden Department of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden Department of Pathology, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden Department of Medicine, Southern Hospital, Karolinska Institutet, Stockholm, Sweden * Corresponding author; email: Eva.Hellstrom-Lindberg{at}medhs.ki.se. Low-risk myelodysplastic syndromes (MDS), including refractory anemia and sideroblastic anemia, are characterized by increased apoptotic death of erythroid progenitors. The signaling pathways that elicit this pathological cell death in MDS have, however, remained unclear. Treatment with erythropoietin in combination with granulocyte colony-stimulating factor (G-CSF) may synergistically improve the anemia in MDS patients, with a concomitant decrease in the number of apoptotic bone marrow precursors. Moreover, we have previously reported that G-CSF inhibits Fas-induced caspase activation in sideroblastic anemia (RARS). The present data demonstrate that almost 50% of erythroid progenitor cells derived from MDS patients exhibit spontaneous release of cytochrome c from mitochondria with ensuing activation of caspase-9, whereas normal erythroid progenitors display neither of these features. G-CSF significantly inhibited cytochrome c release and suppressed apoptosis, most noticeably in cells from sideroblastic anemia patients. Furthermore, inhibition of caspase-9 suppressed both spontaneous and Fas-mediated apoptosis of erythroid progenitors in all low-risk MDS cases studied. We propose that the increased sensitivity of MDS progenitor cells to death receptor stimulation is due to a constitutive activation of the mitochondrial axis of the apoptotic signaling pathway in these cells. These studies yield a mechanistic explanation for the beneficial clinical effects of growth factor administration in MDS patients, and provide a model for the study of growth factor-mediated suppression of apoptosis in other bone marrow disorders. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Hellstrom-Lindberg and M. Cazzola The Role of JAK2 Mutations in RARS and Other MDS Hematology, January 1, 2008; 2008(1): 52 - 59. [Abstract] [Full Text] [PDF] A. Pellagatti, M. Jadersten, A.-M. Forsblom, H. Cattan, B. Christensson, E. K. Emanuelsson, M. 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