Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations

Abstract

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 (∼ 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.