title: Rescue of early-stage myelodysplastic syndrome-deriving erythroid precursors by the ectopic expression of a dominant-negative form of FADD.
abstract: 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.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.
authors.forename: Yann-Erick
authors.initials: YE
authors.lastname: Claessens
authors.forename: Sophie
authors.initials: S
authors.lastname: Park
authors.forename: Anne
authors.initials: A
authors.lastname: Dubart-Kupperschmitt
authors.forename: Virginie
authors.initials: V
authors.lastname: Mariot
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.forename: Stany
authors.initials: S
authors.lastname: Chrétien
authors.forename: François
authors.initials: F
authors.lastname: Dreyfus
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacombe
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.forename: Michaëla
authors.initials: M
authors.lastname: Fontenay
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D041905:Erythroid Cells / Q000378:metabolism* / Q000473:pathology*; D053200:Fas-Associated Death Domain Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D009367:Neoplasm Staging; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases