Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
Biochem Biophys Res Commun. 2014 Jul 18;450(1):837-43. doi: 10.1016/j.bbrc.2014.06.066. Epub 2014 Jun 21.
Acute myeloid leukaemia (AML) is a heterogeneous neoplastic disorder in which a subset of cells function as leukaemia-initiating cells (LICs). In this study, we prospectively evaluated the leukaemia-initiating capacity of AML cells fractionated according to the expression of a nucleolar GTP binding protein, nucleostemin (NS). To monitor NS expression in living AML cells, we generated a mouse AML model in which green fluorescent protein (GFP) is expressed under the control of a region of the NS promoter (NS-GFP). In AML cells, NS-GFP levels were correlated with endogenous NS mRNA. AML cells with the highest expression of NS-GFP were very immature blast-like cells, efficiently formed leukaemia colonies in vitro, and exhibited the highest leukaemia-initiating capacity in vivo. Gene expression profiling analysis revealed that cell cycle regulators and nucleotide metabolism-related genes were highly enriched in a gene set associated with leukaemia-initiating capacity that we termed the 'leukaemia stem cell gene signature'. This gene signature stratified human AML patients into distinct clusters that reflected prognosis, demonstrating that the mouse leukaemia stem cell gene signature is significantly associated with the malignant properties of human AML. Further analyses of gene regulation in leukaemia stem cells could provide novel insights into diagnostic and therapeutic approaches to AML.
急性髓系白血病（AML）是一种异质性肿瘤疾病，其中一部分细胞作为白血病起始细胞（LICs）发挥作用。在这项研究中，我们前瞻性地评估了根据核仁 GTP 结合蛋白核干细胞蛋白（NS）的表达对 AML 细胞进行分离的起始能力。为了监测活 AML 细胞中 NS 的表达，我们生成了一种在 NS 启动子区域（NS-GFP）控制下表达绿色荧光蛋白（GFP）的小鼠 AML 模型。在 AML 细胞中，NS-GFP 水平与内源性 NS mRNA 相关。表达 NS-GFP 水平最高的 AML 细胞是非常不成熟的原始样细胞，能够在体外有效地形成白血病集落，并在体内表现出最高的白血病起始能力。基因表达谱分析显示，细胞周期调节剂和核苷酸代谢相关基因在与我们称为“白血病干细胞基因特征”的白血病起始能力相关的基因集中高度富集。该基因特征将人类 AML 患者分为不同的聚类，反映了预后，表明小鼠白血病干细胞基因特征与人类 AML 的恶性特性显著相关。对白血病干细胞中基因调控的进一步分析可能为 AML 的诊断和治疗方法提供新的见解。
