Clonal selection and asymmetric distribution of human leukemia in murine xenografts revealed by cellular barcoding
Clonal selection and asymmetric distribution of human leukemia in murine xenografts revealed by cellular barcoding
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DOI：
10.1182/blood-2016-12-758250
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发表时间：
2017-06-15
期刊：
影响因子：
20.3
通讯作者：
Bystrykh, Leonid V.
中科院分区：
文献类型：
--
作者：
Belderbos, Mirjam E.;Koster, Taco;Bystrykh, Leonid V.
人类白血病的遗传和表型异质性被认为通过达尔文的选择过程和恶性克隆的进化来推动白血病的进展。然而，缺乏标记，独特地识别个别白血病克隆排除了高分辨率跟踪其克隆动力学。在这里，我们使用细胞条形码分析小鼠异种移植物中患者来源的白血病增殖细胞（LPC）的克隆行为。使用白血病细胞系和诊断骨髓细胞从6例B祖细胞急性淋巴细胞白血病，我们证明，患者来源的异种移植物是高度多克隆的，由数十至数百个LPC克隆。异种移植物中克隆的数量是稳定的，但在连续移植后强烈减少。与克隆组成高度多样化的初级受体相反，连续异种移植物中的克隆组成在同一供体的受体之间高度相似，反映了供体克隆性，支持确定性的、基于克隆大小的克隆选择模型。在几个解剖位置的克隆丰度定量分析确定了2种类型的解剖不对称。首先，克隆体在不同的骨骼之间不对称地分布。第二，克隆组成的骨骼显着不同的髓外网站，显示相似的数量，但不同的克隆大小。总之，这项研究表明，细胞条形码和异种移植提供了一个有用的模型来研究患者来源的LPC克隆的行为，这为癌症干细胞的实验研究和白血病的诊断和治疗的临床方案提供了相关的见解。
Genetic and phenotypic heterogeneity of human leukemia is thought to drive leukemia progression through a Darwinian process of selection and evolution of increasingly malignant clones. However, the lack of markers that uniquely identify individual leukemia clones precludes high-resolution tracing of their clonal dynamics. Here, we use cellular barcoding to analyze the clonal behavior of patient-derived leukemia-propagating cells (LPCs) in murine xenografts. Using a leukemic cell line and diagnostic bone marrow cells from 6 patients with B-progenitor cell acute lymphoblastic leukemia, we demonstrate that patient-derived xenografts were highly polyclonal, consisting of tens to hundreds of LPC clones. The number of clones was stable within xenografts but strongly reduced upon serial transplantation. In contrast to primary recipients, in which clonal composition was highly diverse, clonal composition in serial xenografts was highly similar between recipients of the same donor and reflected donor clonality, supporting a deterministic, clone-size-based model for clonal selection. Quantitative analysis of clonal abundance in several anatomic sites identified 2 types of anatomic asymmetry. First, clones were asymmetrically distributed between different bones. Second, clonal composition in the skeleton significantly differed from extramedullary sites, showing similar numbers but different clone sizes. Altogether, this study shows that cellular barcoding and xenotransplantation providea useful model to study the behavior of patient-derived LPC clones, which provides insights relevant for experimental studies on cancer stem cells and for clinical protocols for the diagnosis and treatment of leukemia.