Rescue of early-stage myelodysplastic syndrome-deriving erythroid precursors by the ectopic expression of a dominant-negative form of FADD

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 Inter...

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Bibliographic Details
Published in:Blood 2005-05, Vol.105 (10), p.4035-4042
Main Authors: Claessens, Yann-Erick, Park, Sophie, Dubart-Kupperschmitt, Anne, Mariot, Virginie, Garrido, Carmen, Chrétien, Stany, Dreyfus, François, Lacombe, Catherine, Mayeux, Patrick, Fontenay, Michaëla
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Adult
Aged
Aged, 80 and over
Apoptosis
Apoptosis Regulatory Proteins
Biological and medical sciences
Caspase 8
Caspases - metabolism
Cell Differentiation
Cells, Cultured
Erythroid Cells - metabolism
Erythroid Cells - pathology
Fas-Associated Death Domain Protein
Female
Gene Expression Regulation, Neoplastic
Genes, Dominant - genetics
Hematologic and hematopoietic diseases
Humans
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Male
Medical sciences
Membrane Glycoproteins - metabolism
Middle Aged
Myelodysplastic Syndromes - genetics
Myelodysplastic Syndromes - metabolism
Myelodysplastic Syndromes - pathology
Myelodysplastic Syndromes - therapy
Neoplasm Staging
Stem Cells - cytology
Stem Cells - metabolism
TNF-Related Apoptosis-Inducing Ligand
Tumor Necrosis Factor-alpha - metabolism
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Summary: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 α (TNF-α) 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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2004-08-3166