Prick Janine, de Haan Gerald, Green Anthony R, Kent David G
Cambridge Institute for Medical Research and Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Exp Hematol. 2014 Oct;42(10):841-51. doi: 10.1016/j.exphem.2014.07.268. Epub 2014 Sep 6.
Myeloproliferative neoplasms (MPNs) are clonal hematological diseases in which cells of the myelo-erythroid lineage are overproduced and patients are predisposed to leukemic transformation. Hematopoietic stem cells are the suspected disease-initiating cells, and these cells must acquire a clonal advantage relative to nonmutant hematopoietic stem cells to perpetuate disease. In 2005, several groups identified a single gain-of-function point mutation in JAK2 that associated with the majority of MPNs, and subsequent studies have led to a comprehensive understanding of the mutational landscape in MPNs. However, confusion still exists as to how a single genetic aberration can be associated with multiple distinct disease entities. Many explanations have been proposed, including JAK2V617F homozygosity, individual patient heterogeneity, and the differential regulation of downstream JAK2 signaling pathways. Several groups have made knock-in mouse models expressing JAK2V617F and have observed divergent phenotypes, each recapitulating some aspects of disease. Intriguingly, most of these models do not observe a strong hematopoietic stem cell self-renewal advantage compared with wild-type littermate controls, raising the question of how a clonal advantage is established in patients with MPNs. This review summarizes the current molecular understanding of MPNs and the diversity of disease phenotypes and proposes that the increased proliferation induced by JAK2V617F applies a selection pressure on the mutant clone that results in highly diverse clonal evolution in individuals.
骨髓增殖性肿瘤（MPNs）是一类克隆性血液系统疾病，其中髓系-红系谱系的细胞过度增殖，患者易发生白血病转化。造血干细胞被怀疑是引发疾病的细胞，这些细胞必须相对于非突变造血干细胞获得克隆优势才能使疾病持续存在。2005年，几个研究小组在JAK2基因中发现了一个与大多数MPNs相关的功能获得性单点突变，随后的研究使人们对MPNs的突变图谱有了全面的了解。然而，对于单一基因畸变如何与多种不同的疾病实体相关联，仍然存在困惑。已经提出了许多解释，包括JAK2V617F纯合性、个体患者异质性以及下游JAK2信号通路的差异调节。几个研究小组构建了表达JAK2V617F的基因敲入小鼠模型，并观察到了不同的表型，每种表型都概括了疾病的某些方面。有趣的是，与野生型同窝对照相比，这些模型中的大多数都没有观察到强大的造血干细胞自我更新优势，这就提出了一个问题，即MPNs患者的克隆优势是如何建立的。这篇综述总结了目前对MPNs的分子理解以及疾病表型的多样性，并提出JAK2V617F诱导的增殖增加对突变克隆施加了选择压力，导致个体中高度多样的克隆进化。
