Loss of Asxl2 leads to myeloid malignancies in mice.
Loss of Asxl2 leads to myeloid malignancies in mice.
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Asxl2 缺失会导致小鼠出现骨髓恶性肿瘤。
DOI：
10.1038/ncomms15456
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发表时间：
2017-06-08
影响因子：
16.6
通讯作者：
Yang FC
中科院分区：
文献类型：
--
作者：
Li J;He F;Zhang P;Chen S;Shi H;Sun Y;Guo Y;Yang H;Man N;Greenblatt S;Li Z;Guo Z;Zhou Y;Wang L;Morey L;Williams S;Chen X;Wang QT;Nimer SD;Yu P;Wang QF;Xu M;Yang FC
ASXL 2在t（8;21）急性髓性白血病患者中经常发生突变。然而，ASXL 2在正常造血和骨髓恶性肿瘤的发病机制中的作用仍然未知。在这里，我们表明小鼠中Asxl 2的缺失导致骨髓增生异常综合征（MDS）样疾病的发展。与野生型对照组相比，Asxl 2 −/−小鼠的骨髓（BM）长期造血干细胞（HSC）和粒细胞-巨噬细胞祖细胞增加。移植了Asxl 2 −/−和Asxl 2 +/− BM细胞的受体由于MDS样疾病或骨髓性白血病的发展而缩短了寿命。配对子细胞测定表明，Asxl 2缺失增强了HSC的自我更新。Asxl 2的缺失改变了Lin−cKit+细胞中HSC自我更新、分化和凋亡关键基因的表达。改变的基因表达与H3 K27 ac和H3 K4 me 1/2失调有关。我们的研究表明，ASXL 2作为一种肿瘤抑制剂，以维持正常的HSC功能。 ASXL 2突变主要发现于具有某些遗传畸变的白血病患者的子集中;然而，该蛋白在正常造血和相关恶性肿瘤中的作用仍不清楚。在这里，作者使用基因敲除小鼠模型来揭示Asxl 2在造血和白血病发生中的作用。
ASXL2 is frequently mutated in acute myeloid leukaemia patients with t(8;21). However, the roles of ASXL2 in normal haematopoiesis and the pathogenesis of myeloid malignancies remain unknown. Here we show that deletion of Asxl2 in mice leads to the development of myelodysplastic syndrome (MDS)-like disease. Asxl2−/− mice have an increased bone marrow (BM) long-term haematopoietic stem cells (HSCs) and granulocyte–macrophage progenitors compared with wild-type controls. Recipients transplanted with Asxl2−/− and Asxl2+/− BM cells have shortened lifespan due to the development of MDS-like disease or myeloid leukaemia. Paired daughter cell assays demonstrate that Asxl2 loss enhances the self-renewal of HSCs. Deletion of Asxl2 alters the expression of genes critical for HSC self-renewal, differentiation and apoptosis in Lin−cKit+ cells. The altered gene expression is associated with dysregulated H3K27ac and H3K4me1/2. Our study demonstrates that ASXL2 functions as a tumour suppressor to maintain normal HSC function. ASXL2 mutations are mostly found in a subset of leukemia patients with certain genetic aberrations; however the role of this protein in normal hematopoiesis and related malignancies is still unclear. Here the authors use a knock-out mouse model to uncover the role of Asxl2 in hematopoiesis and leukemogenesis.