Hematopoietic defects in the Ts1Cje mouse model of Down syndrome
Hematopoietic defects in the Ts1Cje mouse model of Down syndrome
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DOI：
10.1182/blood-2008-06-161422
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发表时间：
2009-02-26
期刊：
影响因子：
20.3
通讯作者：
Scott, Hamish S.
中科院分区：
文献类型：
--
作者：
Carmichael, Catherine L.;Majewski, Ian J.;Scott, Hamish S.
唐氏综合征(DS)患者出生时就有各种造血异常，从相对良性的中性粒细胞增多症和巨核细胞增多症，到更严重的一过性骨髓增殖性疾病(TMD)。在大多数情况下，这些异常在生命的头几个月到几年内就会消失。然而，有时TMD代表一种癌前疾病，发展为急性巨核细胞白血病(AMKL)，通常与获得性GATA1突变有关。为了深入了解这些异常的机制，我们分析了DS的Ts1Cje小鼠模型的造血发育。我们的分析确定了成熟血细胞的缺陷，包括巨噬细胞增多和贫血，以及胎肝和骨髓干细胞和祖细胞功能的异常。尽管有这些缺陷，Ts1Cje小鼠并没有出现类似TMD或AMKL的疾病，这并没有因为GATA1功能等位基因的丧失而改变。因此，GATA1的缺失和21号染色体同源的部分三体结合在一起，似乎不足以在小鼠中诱导TMD或AMKL样表型。(血。2009年；113：1929-1937)
Down syndrome (DS) persons are born with various hematopoietic abnormalities, ranging from relatively benign, such as neutrophilia and macrocytosis, to a more severe transient myeloproliferative disorder (TMD). In most cases, these abnormalities resolve in the first few months to years of life. However, sometimes the TMD represents a premalignant disease that develops into acute megakaryocytic leukemia (AMKL), usually in association with acquired GATA1 mutations. To gain insight into the mechanisms responsible for these abnormalities, we analyzed the hematopoietic development of the Ts1Cje mouse model of DS. Our analyses identified defects in mature blood cells, including macrocytosis and anemia, as well as abnormalities in fetal liver and bone marrow stem and progenitor cell function. Despite these defects, the Ts1Cje mice do not develop disease resembling either TMD or AMKL, and this was not altered by a loss of function allele of Gata1. Thus, loss of Gata1 and partial trisomy of chromosome 21 orthologs, when combined, do not appear to be sufficient to induce TMD or AMKL-like phenotypes in mice. (Blood. 2009; 113: 1929-1937)