title: Trisomy 21 enhances human fetal erythro-megakaryocytic development.
abstract: Children with Down syndrome exhibit 2 related hematopoietic diseases: transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia (AMKL). Both exhibit clonal expansion of blasts with biphenotypic erythroid and megakaryocytic features and contain somatic GATA1 mutations. While altered GATA1 inhibits erythro-megakaryocytic development, less is known about how trisomy 21 impacts blood formation, particularly in the human fetus where TMD and AMKL originate. We used in vitro and mouse transplantation assays to study hematopoiesis in trisomy 21 fetal livers with normal GATA1 alleles. Remarkably, trisomy 21 progenitors exhibited enhanced production of erythroid and megakaryocytic cells that proliferated excessively. Our findings indicate that trisomy 21 itself is associated with cell-autonomous expansion of erythro-megakaryocytic progenitors. This may predispose to TMD and AMKL by increasing the pool of cells susceptible to malignant transformation through acquired mutations in GATA1 and other cooperating genes.
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, PA, USA
authors.forename: Stella T
authors.initials: ST
authors.lastname: Chou
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Opalinska
authors.forename: Yu
authors.initials: Y
authors.lastname: Yao
authors.forename: Myriam A
authors.initials: MA
authors.lastname: Fernandes
authors.forename: Anna
authors.initials: A
authors.lastname: Kalota
authors.forename: John S J
authors.initials: JS
authors.lastname: Brooks
authors.forename: John K
authors.initials: JK
authors.lastname: Choi
authors.forename: Alan M
authors.initials: AM
authors.lastname: Gewirtz
authors.forename: Gwenn-ael
authors.initials: GA
authors.lastname: Danet-Desnoyers
authors.forename: Richard L
authors.initials: RL
authors.lastname: Nemiroff
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D004314:Down Syndrome / Q000196:embryology* / Q000473:pathology; D004912:Erythrocytes / Q000502:physiology*; D015672:Erythroid Precursor Cells / Q000502:physiology; D005260:Female; D016332:Fetal Tissue Transplantation / Q000502:physiology; D006413:Hematopoietic System / Q000196:embryology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000196:embryology / Q000473:pathology; D016031:Liver Transplantation / Q000502:physiology; D008533:Megakaryocytes / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D023461:Myeloid Progenitor Cells / Q000502:physiology; D011247:Pregnancy