Department of Zoology, University of British Columbia, Vancouver, BC, Canada.
Blood. 2010 Jan 7;115(1):38-46. doi: 10.1182/blood-2009-07-230698. Epub 2009 Oct 27.
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.
额外的梳子样蛋白 1（Asxl1）基因是果蝇额外的梳子（Asx）基因的 3 种哺乳动物同源物之一。Asx 很不寻常，因为它需要在果蝇和小鼠中维持 Hox 基因的激活和沉默。Asxl 蛋白的特征是氨基末端同源结构域、与核受体相互作用的结构域和 C 末端植物同源域蛋白-蛋白相互作用结构域。最近对骨髓增生异常综合征（MDS）和慢性骨髓单核细胞白血病（CMML）患者的研究揭示了高频截断突变，这些突变会删除 ASXL1 的 PHD 结构域。在这里，我们表明 Asxl1 在所有分析的造血细胞部分中表达。Asxl1 敲除小鼠表现出淋巴细胞和髓系祖细胞分化频率的缺陷，但多能祖细胞没有缺陷。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，在这种功能丧失模型中，我们没有检测到严重的骨髓增生异常表型或白血病。我们得出结论，Asxl1 是正常造血所必需的。观察到的轻度表型可能是因为其他 Asxl 基因与 Asxl1 具有冗余功能，或者 MDS 或致癌表型可能是由于基因组扩增、基因融合或 Asxl1 的截断导致获得性功能的 Asxl 突变引起的。
