Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations
- 30 November 2008
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 112 (12), 4507-4511
- https://doi.org/10.1182/blood-2008-04-152967
Abstract
Down syndrome (DS) children have a high frequency of acute megakaryoblastic leukemia (AMKL) in early childhood. At least 2 in utero genetic events are required, although 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 (FLs), but not marrows, megakaryocyte erythroid progenitor frequency was increased (55.9% +/- 4% vs 17.1% +/- 3%, CD34(+)CD38(+) cells; P < .001) with common myeloid progenitors (19.6% +/- 2% vs 44.0% +/- 7%) and granulocyte-monocyte (GM) progenitors (15.8% +/- 4% vs 34.5% +/- 9%) commensurately reduced. Clonogenicity of DS-FL versus normal FL CD34(+) cells was markedly increased (78% +/- 7% vs 15% +/- 3%) affecting megakaryocyte-erythroid (similar to 7-fold higher) and GM and colony-forming unit-granulocyte, erythrocyte macrophage, megakaryocyte (CFU-GEMM) progenitors. Replating efficiency of CFU-GEMM was also markedly increased. These data indicate that T21 itself profoundly disturbs FL hemopoiesis and they provide a testable hypothesis to explain the increased susceptibility to GATA1 mutations in DS-AMKL and DS-associated transient myeloproliferative disorder. (Blood. 2008; 112: 4507-4511)This publication has 23 references indexed in Scilit:
- Myeloid leukemia in children 4 years or older with Down syndrome often lacks GATA1 mutation and cytogenetics and risk of relapse are more akin to sporadic AMLLeukemia, 2007
- Myelodysplastic and myeloproliferative disorders in childrenCurrent Opinion in Pediatrics, 2007
- GATA1 mutation and trisomy 21 are required only in haematopoietic cells for development of transient myeloproliferative disorderBritish Journal of Haematology, 2005
- Prenatal origin of GATA1 mutations may be an initiating step in the development of megakaryocytic leukemia in Down syndromeBlood, 2004
- Natural history of GATA1 mutations in Down syndromeBlood, 2004
- Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndromeBlood, 2003
- GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndromeBlood, 2003
- Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesisBlood, 2003
- Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21Blood, 2003
- Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndromeNature Genetics, 2002