Document Detail


Rescue of early-stage myelodysplastic syndrome-deriving erythroid precursors by the ectopic expression of a dominant-negative form of FADD.
MedLine Citation:
PMID:  15677568     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-01-27
Journal Detail:
Title:  Blood     Volume:  105     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-05-03     Completed Date:  2005-06-07     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4035-42     Citation Subset:  AIM; IM    
Affiliation:
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:
Adaptor Proteins, Signal Transducing / 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:
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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