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

• Published in: Blood 2008-12, Vol.112 (12), p.4507-4511
• Main Authors: Tunstall-Pedoe, Oliver, Roy, Anindita, Karadimitris, Anastasios, de la Fuente, Josu, Fisk, Nicholas M., Bennett, Phillip, Norton, Alice, Vyas, Paresh, Roberts, Irene
• Format: Article
• Language: English
• Subjects: Antigens, CD34 - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Count; Congenital Abnormalities - genetics; Congenital Abnormalities - pathology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Down Syndrome - complications; Down Syndrome - genetics; Female; GATA1 Transcription Factor - genetics; Genetic Predisposition to Disease - embryology; Genetic Predisposition to Disease - etiology; Hematologic and hematopoietic diseases; Humans; Leukemia, Megakaryoblastic, Acute - complications; Leukemia, Megakaryoblastic, Acute - embryology; Leukemia, Megakaryoblastic, Acute - genetics; Liver Diseases - complications; Liver Diseases - embryology; Liver Diseases - genetics; Medical sciences; Mutation - physiology; Myeloid Progenitor Cells - metabolism; Myeloid Progenitor Cells - pathology; Pregnancy; Pregnancy Trimester, Second; Time Factors
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-04-152967

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.