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Blood, 15 May 2005, Vol. 105, No. 10, pp. 4035-4042. Prepublished online as a Blood First Edition Paper on January 27, 2005; DOI 10.1182/blood-2004-08-3166. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-08-3166v1 105/10/4035    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 Claessens, Y.-E. Articles by Fontenay, M. Search for Related Content PubMed PubMed Citation Articles by Claessens, Y.-E. Articles by Fontenay, M. Related Collections Hematopoiesis and Stem Cells Neoplasia Apoptosis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Rescue of early-stage myelodysplastic syndrome-deriving erythroid precursors by the ectopic expression of a dominant-negative form of FADD Yann-Erick Claessens, Sophie Park, Anne Dubart-Kupperschmitt, Virginie Mariot, Carmen Garrido, Stany Chrétien, François Dreyfus, Catherine Lacombe, Patrick Mayeux, and Michaëla Fontenay From the Departement d'Hematologie, Institut Cochin, l'Institut National de la Santé et de la Recherche Médicale (INSERM) U567, Centre National de la Recherche Scientifique Unité Mixtes de Recherche (CNRS UMR) 8104, Universite Rene-Descartes, Paris, France; INSERM U517, Faculte de Medecine, Dijon, France; and the Hopital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Service d'Hematologie, Paris, France. Myelodysplastic syndromes (MDSs) are characterized by peripheral blood cytopenia including anemia. We have investigated the implication of the extrinsic pathway of apoptosis in MDS-ineffective erythropoiesis by in vitro expansion of erythroid precursors from early stage (low and intermediate-1 International Prognosis Scoring System [IPSS]) MDS, advanced stage (intermediate-2 IPSS) MDS, and control bone marrow samples. We have previously shown that Fas and its ligand were overexpressed in early stage MDS erythroid cells. Here, we show that caspase-8 activity is significantly increased, whereas the expression of death receptors other than Fas, including the type 1 receptor for tumor necrosis factor (TNF-) and the receptors for the TNF-related apoptosis-inducing ligand (TRAIL), DR4 and DR5, was normal. We also observed that the adapter Fas-associated death domain (FADD) was overexpressed in early stage MDS erythroid cells. Transduction of early stage MDS-derived CD34+ progenitors with a FADD-encoding construct increased apoptosis of erythroid cells and dramatically reduced erythroid burst-forming unit (BFU-E) growth. Transduction of a dominant-negative (dn) mutant of FADD inhibited caspase-8 activity and cell death and rescued BFU-E growth without abrogating erythroid differentiation. These results extend the observation that Fas-dependent activation of caspase-8 accounts for apoptosis of early stage MDS erythroid cells and demonstrate for the first time that FADD is a valuable target to correct ineffective erythropoiesis in these syndromes. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Sathyanarayana, A. Dev, J. Fang, E. Houde, O. Bogacheva, O. Bogachev, M. Menon, S. Browne, A. Pradeep, C. Emerson, et al. EPO receptor circuits for primary erythroblast survival Blood, June 1, 2008; 111(11): 5390 - 5399. [Abstract] [Full Text] [PDF] D. P. Steensma and J. M. Bennett The Myelodysplastic Syndromes: Diagnosis and Treatment Mayo Clin. Proc., January 1, 2006; 81(1): 104 - 130. [Abstract] [Full Text] [PDF]

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