title: Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21.
abstract: The 40-fold increase in childhood megakaryocyte-erythroid and B-cell leukemia in Down syndrome implicates trisomy 21 (T21) in perturbing fetal hematopoiesis. Here, we show that compared with primary disomic controls, primary T21 fetal liver (FL) hematopoietic stem cells (HSC) and megakaryocyte-erythroid progenitors are markedly increased, whereas granulocyte-macrophage progenitors are reduced. Commensurately, HSC and megakaryocyte-erythroid progenitors show higher clonogenicity, with increased megakaryocyte, megakaryocyte-erythroid, and replatable blast colonies. Biased megakaryocyte-erythroid-primed gene expression was detected as early as the HSC compartment. In lymphopoiesis, T21 FL lymphoid-primed multipotential progenitors and early lymphoid progenitor numbers are maintained, but there was a 10-fold reduction in committed PreproB-lymphoid progenitors and the functional B-cell potential of HSC and early lymphoid progenitor is severely impaired, in tandem with reduced early lymphoid gene expression. The same pattern was seen in all T21 FL samples and no samples had GATA1 mutations. Therefore, T21 itself causes multiple distinct defects in FL myelo- and lymphopoiesis.
authors.affiliation: Centre for Haematology, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Anindita
authors.initials: A
authors.lastname: Roy
authors.forename: Gillian
authors.initials: G
authors.lastname: Cowan
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Mead
authors.forename: Sarah
authors.initials: S
authors.lastname: Filippi
authors.forename: Georg
authors.initials: G
authors.lastname: Bohn
authors.forename: Aristeidis
authors.initials: A
authors.lastname: Chaidos
authors.forename: Oliver
authors.initials: O
authors.lastname: Tunstall
authors.forename: Jerry K Y
authors.initials: JK
authors.lastname: Chan
authors.forename: Mahesh
authors.initials: M
authors.lastname: Choolani
authors.forename: Phillip
authors.initials: P
authors.lastname: Bennett
authors.forename: Sailesh
authors.initials: S
authors.lastname: Kumar
authors.forename: Deborah
authors.initials: D
authors.lastname: Atkinson
authors.forename: Josephine
authors.initials: J
authors.lastname: Wyatt-Ashmead
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.forename: Michael P H
authors.initials: MP
authors.lastname: Stumpf
authors.forename: Katerina
authors.initials: K
authors.lastname: Goudevenou
authors.forename: David
authors.initials: D
authors.lastname: O'Connor
authors.forename: Stella T
authors.initials: ST
authors.lastname: Chou
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
authors.forename: Anastasios
authors.initials: A
authors.lastname: Karadimitris
authors.forename: Sten Eirik
authors.initials: SE
authors.lastname: Jacobsen
authors.forename: Paresh
authors.initials: P
authors.lastname: Vyas
authors.forename: Irene
authors.initials: I
authors.lastname: Roberts
mesh_terms: D002454:Cell Differentiation; D019070:Cell Lineage; D004314:Down Syndrome; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000196:embryology* / Q000473:pathology