| Rescue of early-stage myelodysplastic syndrome-deriving erythroid precursors by the ectopic expression of a dominant-negative form of FADD. | |
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MedLine Citation:
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PMID: 15677568 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 alpha (TNF-alpha) 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. |
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Authors:
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Yann-Erick Claessens; Sophie Park; Anne Dubart-Kupperschmitt; Virginie Mariot; Carmen Garrido; Stany Chrétien; François Dreyfus; Catherine Lacombe; Patrick Mayeux; Michaëla Fontenay |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2005-01-27 |
Journal Detail:
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Title: Blood Volume: 105 ISSN: 0006-4971 ISO Abbreviation: Blood Publication Date: 2005 May |
Date Detail:
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Created Date: 2005-05-03 Completed Date: 2005-06-07 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 4035-42 Citation Subset: AIM; IM |
Affiliation:
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Departement d'Hematologie, Institut Cochin, l'Institut National de la Santé et de la Recherche Médicale U567, Centre National de la Recherche Scientifique Unité Mixtes de Recherche 8104, Universite Rene-Descartes, Paris, France. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing
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genetics*,
metabolism* Adult Aged Aged, 80 and over Apoptosis Apoptosis Regulatory Proteins Caspase 8 Caspases / metabolism Cell Differentiation* Cells, Cultured Erythroid Cells / metabolism*, pathology* Fas-Associated Death Domain Protein Female Gene Expression Regulation, Neoplastic Genes, Dominant / genetics Humans Male Membrane Glycoproteins / metabolism Middle Aged Myelodysplastic Syndromes / genetics, metabolism*, pathology, therapy* Neoplasm Staging Stem Cells / cytology, metabolism TNF-Related Apoptosis-Inducing Ligand Tumor Necrosis Factor-alpha / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Proteins, Signal Transducing; 0/Apoptosis Regulatory Proteins; 0/FADD protein, human; 0/Fas-Associated Death Domain Protein; 0/Membrane Glycoproteins; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFSF10 protein, human; 0/Tumor Necrosis Factor-alpha; EC 3.4.22.-/CASP8 protein, human; EC 3.4.22.-/Caspase 8; EC 3.4.22.-/Caspases |
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