title: Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations.
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 ( approximately 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.
authors.affiliation: Department of Haematology, Imperial College London and Imperial Healthcare NHS Trust, London, United Kingdom.
authors.forename: Oliver
authors.initials: O
authors.lastname: Tunstall-Pedoe
authors.forename: Anindita
authors.initials: A
authors.lastname: Roy
authors.forename: Anastasios
authors.initials: A
authors.lastname: Karadimitris
authors.forename: Josu
authors.initials: J
authors.lastname: de la Fuente
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Fisk
authors.forename: Phillip
authors.initials: P
authors.lastname: Bennett
authors.forename: Alice
authors.initials: A
authors.lastname: Norton
authors.forename: Paresh
authors.initials: P
authors.lastname: Vyas
authors.forename: Irene
authors.initials: I
authors.lastname: Roberts
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D002452:Cell Count; D000013:Congenital Abnormalities / Q000235:genetics* / Q000473:pathology; D004314:Down Syndrome / Q000150:complications* / Q000235:genetics*; D005260:Female; D050982:GATA1 Transcription Factor / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000196:embryology / Q000209:etiology*; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000150:complications / Q000196:embryology / Q000235:genetics; D008107:Liver Diseases / Q000150:complications / Q000196:embryology / Q000235:genetics*; D009154:Mutation / Q000502:physiology; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D013997:Time Factors
chemical_list: D018952:Antigens, CD34; D050982:GATA1 Transcription Factor