GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia
GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia
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DOI：
10.1038/leu.2013.373
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发表时间：
2014-06-01
期刊：
影响因子：
11.4
通讯作者：
Klusmann, J-H
中科院分区：
文献类型：
--
作者：
Maroz, A.;Stachorski, L.;Klusmann, J-H
短暂性白血病（TL）在5-10%的唐氏综合征（DS）新生儿中很明显，与n端截断GATA1突变（GATA1s）有关。在这里，我们报告了tl细胞克隆在相当一部分患者中产生丰富的嗜酸性粒细胞。来自TL和嗜酸性粒细胞患者的分类嗜酸性粒细胞与分类的TL原细胞携带相同的GATA1s突变，这与它们的克隆起源一致。TL细胞表现出嗜酸性细胞的遗传程序特征，并在体外沿嗜酸性细胞谱系分化。同样，野生型CD34（+）造血干细胞和祖细胞中Gata1s的异位表达，而不是Gata1的异位表达，在体外诱导嗜酸性早幼粒细胞的过度增殖。尽管GATA1s保留了GATA1通过占领其启动子区域诱导嗜酸性粒细胞基因的功能，但GATA1s抑制致癌MYC和促增殖E2F转录网络的能力受损。染色质免疫沉淀测序（ChIP-seq）显示MYC启动子上GATA1s的占用减少。敲低MYC或e2f的专一合作伙伴DP1，挽救了gata1s诱导的超增殖表型。与此一致的是，在Gata1（Delta e2）敲入小鼠中，终端嗜酸性粒细胞成熟被阻断，只表达Gata1s，导致嗜酸性粒细胞前体在血液和骨髓中积累。这些数据表明，GATA1的n端截断突变与DS患者的克隆性嗜酸性粒细胞增多有直接关系。
Transient leukemia (TL) is evident in 5-10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1 mutations (GATA1s). Here we report that TL-cell clones generate abundant eosinophils in a substantial fraction of patients. Sorted eosinophils from patients with TL and eosinophilia carried the same GATA1s mutations as sorted TL blasts, consistent with their clonal origin. TL blasts exhibited a genetic program characteristic of eosinophils and differentiated along the eosinophil lineage in vitro. Similarly, ectopic expression of Gata1s, but not Gata1, in wild-type CD34(+)-hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro. Although GATA1s retained the function of GATA1 to induce eosinophil genes by occupying their promoter regions, GATA1s was impaired in its ability to repress oncogenic MYC and the pro-proliferative E2F transcription network. Chromatin Immunoprecipitation Sequencing (ChIP-seq) indicated reduced GATA1s occupancy at the MYC promoter. Knockdown of MYC, or the obligate E2F-cooperation partner DP1, rescued the GATA1s-induced hyperproliferative phenotype. In agreement, terminal eosinophil maturation was blocked in Gata1(Delta e2) knockin mice, exclusively expressing Gata1s, leading to accumulation of eosinophil precursors in blood and bone marrow. These data suggest a direct relationship between the N-terminal truncating mutations of GATA1 and clonal eosinophilia in DS patients.