Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome
Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome
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DOI：
10.1182/blood-2009-06-227629
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发表时间：
2010-04-08
期刊：
影响因子：
20.3
通讯作者：
Tybulewicz, Victor L. J.
中科院分区：
文献类型：
--
作者：
Alford, Kate A.;Slender, Amy;Tybulewicz, Victor L. J.
人类21号染色体三体（Hsa21）导致唐氏综合症（DS），这是一种影响生理许多方面的疾病，包括造血。DS患儿急性淋巴母细胞白血病和急性巨核母细胞白血病（AMKL）发病率显著增高；DS新生儿表现为一过性骨髓增生性疾病（TMD），一种白血病前期的AMKL。TMD和DS-AMKL几乎总是携带GATA1的获得性突变，导致截断蛋白（GATA1）的唯一合成，这表明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是如何导致造血异常的，我们研究了Tc1小鼠DS模型，它携带了一个几乎完整的自由分离的Hsa21拷贝，是目前最完整的DS模型。我们发现，虽然Tc1小鼠不会发展成白血病，但它们有巨细胞性贫血和增加的髓外造血。在Tc1小鼠中引入GATA1s会导致巨核生成的协同增加，但不会导致白血病或tmd样表型，这表明大约80%的Hsa21的GATA1s和三体会干扰巨核生成，但不足以诱导白血病。(血。2010;115 (14):2928 - 2937)
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)