Hematopoietic progenitor cell deficiency in fetuses and children affected by Down's syndrome.
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.
Holmes
Denise K
DK
Stem Cell Research Group, Royal Manchester Children's Hospital, Manchester, UK.
Bates
Nicola
N
Murray
Mary
M
Ladusans
E J
EJ
Morabito
Antonino
A
Bolton-Maggs
Paula H B
PH
Johnston
Tracey A
TA
Walkenshaw
Steve
S
Wynn
Robert F
RF
Bellantuono
Ilaria
I
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
D050982:GATA1 Transcription Factor