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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4507-4511.
Prepublished online as a Blood First Edition Paper on August 8, 2008; DOI 10.1182/blood-2008-04-152967.
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Submitted April 18, 2008
Accepted July 26, 2008
Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations
Oliver Tunstall-Pedoe, Anindita Roy, Anastasios Karadimitris, Josu de la Fuente, Nicholas M Fisk, Phillip Bennett, Alice Norton, Paresh Vyas, and Irene Roberts*
Department of Haematology, Imperial College London, London, United Kingdom
Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
Department of Haematology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
* Corresponding author; email: irene.roberts{at}imperial.ac.uk.
Down syndrome (DS) children have a high frequency of acute megakaryoblastic leukemia (AMKL) in early childhood. At least two in utero genetic events are required, though not sufficient, for DS-AMKL: trisomy 21 (T21) and N-terminal-truncating GATA1 mutations. To investigate the role of T21 in DS-AMKL we compared second trimester hemopoiesis in DS without GATA1 mutations to gestation-matched normal controls. In all DS fetal livers (FL), but not marrows, megakaryocyte-erythroid progenitor frequency was increased (55.9±4vs17.1±3% CD34+/CD38+ cells;p<0.001) with CMP (19.6±2vs.44.0±7%) and GMP (15.8±4vs34.5±9%) commensurately reduced. Clonogenicity of DS-FL vs. normal FL CD34+ cells was markedly increased (78±7vs.15±3%) affecting megakaryocyte-erythroid (~7-fold higher) and G/GM/M and CFU-GEMM progenitors. Replating efficiency of CFU-GEMM was also markedly increased. These data indicate T21 itself profoundly disturbs FL hemopoiesis, provide a testable hypothesis to explain the prevalence of GATA1 mutations in DS and have wider implications for T21-mediated effects on non-hemopoietic as well as hemopoietic stem/progenitor populations.
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