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Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome

Alford, KA; Slender, A; Vanes, L; Li, Z; Fisher, EMC; Nizetic, D; Orkin, SH; ... Tybulewicz, VLJ; + view all (2010) Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome. BLOOD , 115 (14) 2928 - 2937. 10.1182/blood-2009-06-227629.

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Abstract

Trisomy of human chromosome 21 (Hsa21) results in Down syndrome (DS), a disorder that affects many aspects of physiology, including hematopoiesis. DS children have greatly increased rates of acute lymphoblastic leukemia and acute megakaryoblastic leukemia (AMKL); DS newborns present with transient myeloproliferative disorder (TMD), a preleukemic form of AMKL. TMD and DS-AMKL almost always carry an acquired mutation in GATA1 resulting in exclusive synthesis of a truncated protein (GATA1s), suggesting that both trisomy 21 and GATA1 mutations are required for leukemogenesis. To gain further understanding of how Hsa21 contributes to hematopoietic abnormalities, we examined the Tc1 mouse model of DS, which carries an almost complete freely segregating copy of Hsa21, and is the most complete model of DS available. We show that although Tc1 mice do not develop leukemia, they have macrocytic anemia and increased extramedullary hematopoiesis. Introduction of GATA1s into Tc1 mice resulted in a synergistic increase in megakaryopoiesis, but did not result in leukemia or a TMD-like phenotype, demonstrating that GATA1s and trisomy of approximately 80% of Hsa21 perturb megakaryopoiesis but are insufficient to induce leukemia. (Blood. 2010;115(14):2928-2937)

Type: Article
Title: Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome
DOI: 10.1182/blood-2009-06-227629
Keywords: ACUTE MEGAKARYOBLASTIC LEUKEMIA, GATA1 MUTATIONS, MYELOPROLIFERATIVE DISORDER, HEMATOLOGICAL ABNORMALITIES, ACQUIRED MUTATIONS, FETAL LIVER, TRISOMY-21, LEUKEMOGENESIS, GENE, HUMAN-CHROMOSOME-21
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Neurodegenerative Diseases
URI: http://discovery.ucl.ac.uk/id/eprint/170486
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