Stem cell gene expression programs influence clinical outcome in human leukemia
Stem cell gene expression programs influence clinical outcome in human leukemia
复制标题
DOI：
10.1038/nm.2415
复制
发表时间：
2011-09-01
期刊：
影响因子：
82.9
通讯作者：
Dick, John E.
中科院分区：
文献类型：
--
作者：
Eppert, Kolja;Takenaka, Katsuto;Dick, John E.
异种移植研究表明，一些实体瘤和白血病组织为由癌症干细胞（CSC）维持的细胞层级。尽管CSC模型有希望，但其在人类中的相关性仍然不确定。在这里，我们表明，急性髓性白血病（AML）遵循CSC模型的基础上，分选多个群体从每个16个主要的人类AML样本，并确定其中包含白血病干细胞（LSC）使用敏感的异种移植试验。对所有功能验证群体的基因表达分析产生了LSC特异性特征。类似地，建立了造血干细胞（HSC）基因签名。生物信息学分析确定了LSC和HSC共享的核心转录程序，揭示了“干性”特性的分子机制。这两个干细胞项目都是患者生存率的高度显著的独立预测因子，并且在现有的预后特征中被发现。因此，干性的决定因素影响AML的临床结果，确定LSC是临床相关的，而不是异种移植的伪影。
Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). Despite the promise of the CSC model, its relevance in humans remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying 'stemness' properties. Both stem cell programs were highly significant independent predictors of patient survival and were found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.