Single-cell approaches identify the molecular network driving malignant hematopoietic stem cell self-renewal
Single-cell approaches identify the molecular network driving malignant hematopoietic stem cell self-renewal
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DOI：
10.1182/blood-2017-12-821066
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发表时间：
2018-08-23
期刊：
影响因子：
20.3
通讯作者：
Kent, David G.
中科院分区：
文献类型：
--
作者：
Shepherd, Mairi S.;Li, Juan;Kent, David G.
单细胞技术的最新进展使异质性细胞群体的研究能够达到以前无法达到的分辨率。在这里，我们使用JAK2V617F突变骨髓增生性肿瘤（mpn）作为模型，应用这些方法来解决小鼠造血干细胞（hsc）中驱动疾病的分子机制。单细胞基因表达和功能分析鉴定出JAK2V617F突变型造血干细胞的一个亚群，显示出有缺陷的自我更新。通过将JAK2V617F小鼠与缺乏TET2 （MPN患者中最常见的计算基因）的小鼠杂交，可以在单个HSC水平上挽救这种缺陷。jak2v617f突变型hsc的单细胞基因表达谱显示特异性调节基因的缺失，其中一些在单个TET2/JAK2突变型hsc中恢复到正常水平。其中，在jak2突变的hsc中，Bmi1以及较小程度上的Pbx1和Meis1过表达可以驱动疾病表型，并在功能分析中保持持久的干细胞自我更新。总之，这些单细胞方法完善了参与mpn克隆扩增的分子，并对解构正常和恶性干细胞的分子网络具有广泛的意义。
Recent advances in single-cell technologies have permitted the investigation of heterogeneous cell populations at previously unattainable resolution. Here we apply such approaches to resolve the molecular mechanisms driving disease in mouse hematopoietic stem cells (HSCs), using JAK2V617F mutant myeloproliferative neoplasms (MPNs) as a model. Single-cell gene expression and functional assays identified a subset of JAK2V617F mutant HSCs that display defective self-renewal. This defect is rescued at the single HSC level by crossing JAK2V617F mice with mice lacking TET2, the most commonly comutated gene in patients with MPN. Single-cell gene expression profiling of JAK2V617F-mutant HSCs revealed a loss of specific regulator genes, some of which were restored to normal levels in single TET2/JAK2 mutant HSCs. Of these, Bmi1 and, to a lesser extent, Pbx1 and Meis1 overexpression in JAK2-mutant HSCs could drive a disease phenotype and retain durable stem cell self-renewal in functional assays. Together, these single-cell approaches refine the molecules involved in clonal expansion of MPNs and have broad implications for deconstructing the molecular network of normal and malignant stem cells.