Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, UK.
Blood. 2010 Apr 8;115(14):2928-37. doi: 10.1182/blood-2009-06-227629. Epub 2010 Feb 12.
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.
人类 21 号染色体三体（Hsa21）导致唐氏综合征（DS），这是一种影响生理多方面的疾病，包括造血。DS 儿童的急性淋巴细胞白血病和急性巨核细胞白血病（AMKL）发病率大大增加；DS 新生儿出现短暂性髓系增生异常（TMD），这是 AMKL 的一种前白血病形式。TMD 和 DS-AMKL 几乎总是携带 GATA1 的获得性突变，导致截短蛋白（GATA1s）的特异性合成，表明 21 三体和 GATA1 突变都是白血病发生所必需的。为了进一步了解 Hsa21 如何导致造血异常，我们研究了 Tc1 小鼠的 DS 模型，该模型携带几乎完整的可自由分离的 Hsa21 拷贝，是目前可用的最完整的 DS 模型。我们表明，尽管 Tc1 小鼠不会发展为白血病，但它们患有巨红细胞性贫血和骨髓外造血增加。将 GATA1s 导入 Tc1 小鼠中会协同增加巨核细胞生成，但不会导致白血病或 TMD 样表型，表明 GATA1s 和 Hsa21 的大约 80%的三体扰乱巨核细胞生成，但不足以诱导白血病。
