Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia
Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia
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DOI：
10.1182/blood-2009-07-230698
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发表时间：
2010-01-07
期刊：
影响因子：
20.3
通讯作者：
Brock, Hugh W.
中科院分区：
文献类型：
--
作者：
Fisher, Cynthia L.;Pineault, Nicolas;Brock, Hugh W.
Asxl 1（Additional sex combs like 1）基因是果蝇Asx（Additional sex combs）基因的3个哺乳动物同源基因之一。Asx是不寻常的，因为它需要在苍蝇和小鼠中维持Hox基因的激活和沉默。Asxl蛋白的特征在于氨基末端同源结构域、核受体的相互作用结构域和C-末端植物同源结构域蛋白-蛋白相互作用结构域。最近一项对骨髓增生异常综合征（MDS）和慢性粒单核细胞白血病（CMML）患者的研究显示，缺失ASXL 1 PHD结构域的截短突变发生率很高。在这里，我们表明，Asxl 1的表达在所有造血细胞组分分析。asxl 1基因敲除小鼠表现出淋巴和髓系祖细胞分化频率的缺陷，但在多能祖细胞中没有。我们没有检测到对造血干细胞或外周血的影响。值得注意的是，我们没有检测到严重的骨髓增生异常表型或白血病在这个功能丧失模型。我们的结论是，Asxl 1是需要正常的造血。观察到的轻度表型可能是因为其他Asxl基因与Asxl 1具有冗余功能，或者MDS或致癌表型可能是由Asxl 1的基因组扩增、基因融合或截短引起的功能获得性Asxl突变引起的。（血。2010;115：38-46）
The Additional sex combs like 1 (Asxl1) gene is 1 of 3 mammalian homologs of the Additional sex combs (Asx) gene of Drosophila. Asx is unusual because it is required to maintain both activation and silencing of Hox genes in flies and mice. Asxl proteins are characterized by an amino terminal homology domain, by interaction domains for nuclear receptors, and by a C-terminal plant homeodomain protein-protein interaction domain. A recent study of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) revealed a high incidence of truncation mutations that would delete the PHD domain of ASXL1. Here, we show that Asxl1 is expressed in all hematopoietic cell fractions analyzed. Asxl1 knockout mice exhibit defects in frequency of differentiation of lymphoid and myeloid progenitors, but not in multipotent progenitors. We do not detect effects on hematopoietic stem cells, or in peripheral blood. Notably, we do not detect severe myelodysplastic phenotypes or leukemia in this loss-of-function model. We conclude that Asxl1 is needed for normal hematopoiesis. The mild phenotypes observed may be because other Asxl genes have redundant function with Asxl1, or alternatively, MDS or oncogenic phenotypes may result from gain-of-function Asxl mutations caused by genomic amplification, gene fusion, or truncation of Asxl1. (Blood. 2010;115:38-46)