Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis.
Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis.
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DOI：
10.1016/j.cell.2015.05.047
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发表时间：
2015-07-02
期刊：
影响因子：
64.5
通讯作者：
Nolan GP
中科院分区：
文献类型：
--
作者：
Levine JH;Simonds EF;Bendall SC;Davis KL;Amir el-AD;Tadmor MD;Litvin O;Fienberg HG;Jager A;Zunder ER;Finck R;Gedman AL;Radtke I;Downing JR;Pe'er D;Nolan GP
急性髓性白血病（AML）表现为表型和功能多样的细胞，通常在同一患者体内。肿瘤内表型和功能异质性主要通过物理分选实验联系起来，该实验假设功能不同的亚群可以通过表面表型前瞻性地分离。事实证明，这种假设是有问题的，因此我们开发了一种数据驱动的方法。使用质谱细胞仪，我们同时分析了数百万健康和白血病细胞的表面和细胞内信号蛋白。我们开发了PhenoGraph，它在算法上定义了高维单细胞数据中的表型。PhenoGraph显示白血病原始细胞的表面表型不一定反映其细胞内状态。使用造血祖细胞，我们定义了一种基于信号传导的细胞表型测量方法，这导致了一种基因表达特征的分离，该特征可预测独立队列的存活率。这项研究提出了大规模分析单细胞异质性的新方法，并证明了它们的实用性，从而深入了解AML的病理生理学。
Acute myeloid leukemia (AML) manifests as phenotypically and functionally diverse cells, often within the same patient. Intratumor phenotypic and functional heterogeneity have been linked primarily by physical sorting experiments, which assume that functionally distinct subpopulations can be prospectively isolated by surface phenotypes. This assumption has proven problematic and we therefore developed a data-driven approach. Using mass cytometry, we profiled surface and intracellular signaling proteins simultaneously in millions of healthy and leukemic cells. We developed PhenoGraph, which algorithmically defines phenotypes in high-dimensional single-cell data. PhenoGraph revealed that the surface phenotypes of leukemic blasts do not necessarily reflect their intracellular state. Using hematopoietic progenitors, we defined a signaling-based measure of cellular phenotype, which led to isolation of a gene expression signature that was predictive of survival in independent cohorts. This study presents new methods for large-scale analysis of single-cell heterogeneity and demonstrates their utility, yielding insights into AML pathophysiology.