Hematopoietic progenitor cell deficiency in fetuses and children affected by Down's syndrome
Hematopoietic progenitor cell deficiency in fetuses and children affected by Down's syndrome
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DOI：
10.1016/j.exphem.2006.10.013
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发表时间：
2006-12-01
影响因子：
2.6
通讯作者：
Bellantuono, Ilaria
中科院分区：
文献类型：
--
作者：
Holmes, Denise K.;Bates, Nicola;Bellantuono, Ilaria
目标.唐氏综合征（DS）患者发生骨髓恶性肿瘤的风险增加，这与转录因子加塔-1的外显子2突变有关。人们认识到，有加速端粒缩短的儿童血液细胞的DS类似的条件，如范可尼贫血和先天性角化不良。后一种情况与干细胞缺乏和克隆改变有关，包括急性髓性白血病。在这项研究中，我们解决了以下问题：1）加速端粒缩短是否与DS个体的祖细胞/干细胞缺乏相关，易发生克隆变化; 2）干细胞/祖细胞数量减少是否先于加塔-1外显子2突变的发生。对DS患儿和年龄匹配的血液健康对照组的胎儿（孕23-35周）外周血和/或骨髓进行端粒长度、干/祖细胞含量和加塔-1外显子2突变分析。我们发现，造血干/祖细胞缺乏和端粒缩短发生在胎儿期DS的个人。此外，低数量祖细胞的存在与加塔-1外显子2突变无关。我们认为干细胞缺乏可能是DS白血病发展的主要诱发因素。(c)2006年国际实验血液学学会。爱思唯尔公司出版
Objectives. There is an increased risk of myeloid malignancy in individuals with Down's syndrome (DS), which is associated with a mutation in exon 2 of the transcription factor GATA-1. It is recognized that there is accelerated telomere shortening in blood cells of children with DS similar to that in conditions such as Fanconi anemia and dyskeratosis congenita. The latter conditions are associated with stem cell deficiency and clonal change, including acute myeloid leukemia. In this study we address the questions 1) whether the accelerated telomere shortening is associated with progenitor/stem cell deficiency in individuals with DS, predisposing to clonal change and 2) whether the occurrence of reduced numbers of stem/progenitor cells precede the incidence of mutations in exon 2 of GATA-1.Material and methods. Peripheral blood from fetuses (23-35 weeks gestation) and/or bone marrow from children affected by DS and age-matched hematologically healthy controls were analyzed for telomere length, content of stem/progenitor cells, and mutations in exon 2 of GATA-1.Results. We found that hematopoietic stem/progenitor cell deficiency and telomere shortening occurs in individuals with DS in fetal life. Moreover, the presence of a low number of progenitor cells was not associated with mutations in exon 2 of GATA-1.Conclusions. We propose that stem cell deficiency may be a primary predisposing event to DS leukemia development. (c) 2006 International Society for Experimental Hematology. Published by Elsevier Inc.