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

Blood. 2005 May 15;105(10):4035-42. doi: 10.1182/blood-2004-08-3166. Epub 2005 Jan 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • 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
  • Humans
  • Male
  • 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


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Membrane Glycoproteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • CASP8 protein, human
  • Caspase 8
  • Caspases