title: Hematopoietic progenitor cell deficiency in fetuses and children affected by Down's syndrome.
abstract: OBJECTIVE
  There is an increased risk of myeloid malignancy in individuals with Down's syndrome (DS), which is associated with a mutation in exon 2 of the transcription factor GATA-1. It is recognized that there is accelerated telomere shortening in blood cells of children with DS similar to that in conditions such as Fanconi anemia and dyskeratosis congenita. The latter conditions are associated with stem cell deficiency and clonal change, including acute myeloid leukemia. In this study we address the questions 1) whether the accelerated telomere shortening is associated with progenitor/stem cell deficiency in individuals with DS, predisposing to clonal change and 2) whether the occurrence of reduced numbers of stem/progenitor cells precede the incidence of mutations in exon 2 of GATA-1.
  
  
  METHODS
  Peripheral blood from fetuses (23-35 weeks gestation) and/or bone marrow from children affected by DS and age-matched hematologically healthy controls were analyzed for telomere length, content of stem/progenitor cells, and mutations in exon 2 of GATA-1.
  
  
  RESULTS
  We found that hematopoietic stem/progenitor cell deficiency and telomere shortening occurs in individuals with DS in fetal life. Moreover, the presence of a low number of progenitor cells was not associated with mutations in exon 2 of GATA-1.
  
  
  CONCLUSIONS
  We propose that stem cell deficiency may be a primary predisposing event to DS leukemia development.
authors.affiliation: Stem Cell Research Group, Royal Manchester Children's Hospital, Manchester, UK.
authors.forename: Denise K
authors.initials: DK
authors.lastname: Holmes
authors.forename: Nicola
authors.initials: N
authors.lastname: Bates
authors.forename: Mary
authors.initials: M
authors.lastname: Murray
authors.forename: E J
authors.initials: EJ
authors.lastname: Ladusans
authors.forename: Antonino
authors.initials: A
authors.lastname: Morabito
authors.forename: Paula H B
authors.initials: PH
authors.lastname: Bolton-Maggs
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Johnston
authors.forename: Steve
authors.initials: S
authors.lastname: Walkenshaw
authors.forename: Robert F
authors.initials: RF
authors.lastname: Wynn
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bellantuono
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004314:Down Syndrome / Q000235:genetics* / Q000473:pathology*; D005091:Exons; D005333:Fetus; D050982:GATA1 Transcription Factor / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007223:Infant; D009154:Mutation; D016615:Telomere / Q000235:genetics
chemical_list: D050982:GATA1 Transcription Factor