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首页> 外文期刊>British Journal of Haematology >Silencing of ASXL1 impairs the granulomonocytic lineage potential of human CD34+ progenitor cells
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Silencing of ASXL1 impairs the granulomonocytic lineage potential of human CD34+ progenitor cells

机译：沉默ASXL1会破坏人类CD34 +祖细胞的粒单核细胞谱系潜能

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The ASXL1 gene encodes a chromatin-binding protein involved in epigenetic regulation in haematopoietic cells. Loss-of-function ASXL1 mutations occur in patients with a range of myeloid malignancies and are associated with adverse outcome. We have used lentiviral-based shRNA technology to investigate the effects of ASXL1 silencing on cell proliferation, apoptosis, myeloid differentiation and global gene expression in human CD34+ cells differentiated along the myeloid lineage in vitro. ASXL1-deficient cells showed a significant decrease in the generation of CD11b+ and CD15+ cells, implicating impaired granulomonocytic differentiation. Furthermore, colony-forming assays showed a significant increase in the number of multipotent mixed lineage colony-forming unit (CFU-GEMM) colonies and a significant decrease in the numbers of granulocyte-macrophage CFU (CFU-GM) and granulocyte CFU (CFU-G) colonies in ASXL1-deficient cells. Our data suggests that ASXL1 knockdown perturbs human granulomonocytic differentiation. Gene expression profiling identified many deregulated genes in the ASXL1-deficient cells differentiated along the granulomonocytic lineage, and pathway analysis showed that the most significantly deregulated pathway was the LXR/RXR activation pathway. ASXL1 may play a key role in recruiting the polycomb repressor complex 2 (PRC2) to specific loci, and we found over-representation of PRC2 targets among the deregulated genes in ASXL1-deficient cells. These findings shed light on the functional role of ASXL1 in human myeloid differentiation. ? 2013 Blackwell Publishing Ltd.
机译：ASXL1基因编码参与造血细胞表观遗传调控的染色质结合蛋白。功能丧失的ASXL1突变发生在患有一系列髓样恶性肿瘤的患者中，并与不良后果相关。我们已使用基于慢病毒的shRNA技术来研究ASXL1沉默对体外沿髓系世系分化的人CD34 +细胞中细胞增殖，凋亡，髓系分化和全局基因表达的影响。缺乏ASXL1的细胞显示CD11b +和CD15 +细胞的生成显着减少，这意味着颗粒单核细胞分化受损。此外，菌落形成分析显示多能混合谱系菌落形成单位（CFU-GEMM）菌落数量显着增加，粒细胞巨噬细胞CFU（CFU-GM）和粒细胞CFU（CFU- G）ASXL1缺陷细胞中的集落。我们的数据表明，ASXL1敲低扰动人类颗粒单核细胞分化。基因表达谱鉴定了沿粒单核细胞系分化的ASXL1缺陷细胞中许多失调的基因，通路分析表明，最显着失调的通路是LXR / RXR激活通路。 ASXL1可能在将多梳阻遏物复合物2（PRC2）募集到特定基因座中起关键作用，并且我们发现ASXL1缺陷细胞中放松调节的基因中PRC2目标的过度表达。这些发现揭示了ASXL1在人类骨髓分化中的功能作用。 ？ 2013布莱克威尔出版有限公司

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