Lundberg Pontus, Takizawa Hitoshi, Kubovcakova Lucia, Guo Guoji, Hao-Shen Hui, Dirnhofer Stephan, Orkin Stuart H, Manz Markus G, Skoda Radek C
Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
Division of Hematology, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland.
J Exp Med. 2014 Oct 20;211(11):2213-30. doi: 10.1084/jem.20131371. Epub 2014 Oct 6.
The majority of patients with myeloproliferative neoplasms (MPNs) carry a somatic JAK2-V617F mutation. Because additional mutations can precede JAK2-V617F, it is questioned whether JAK2-V617F alone can initiate MPN. Several mouse models have demonstrated that JAK2-V617F can cause MPN; however, in all these models disease was polyclonal. Conversely, cancer initiates at the single cell level, but attempts to recapitulate single-cell disease initiation in mice have thus far failed. We demonstrate by limiting dilution and single-cell transplantations that MPN disease, manifesting either as erythrocytosis or thrombocytosis, can be initiated clonally from a single cell carrying JAK2-V617F. However, only a subset of mice reconstituted from single hematopoietic stem cells (HSCs) displayed MPN phenotype. Expression of JAK2-V617F in HSCs promoted cell division and increased DNA damage. Higher JAK2-V617F expression correlated with a short-term HSC signature and increased myeloid bias in single-cell gene expression analyses. Lower JAK2-V617F expression in progenitor and stem cells was associated with the capacity to stably engraft in secondary recipients. Furthermore, long-term repopulating capacity was also present in a compartment with intermediate expression levels of lineage markers. Our studies demonstrate that MPN can be initiated from a single HSC and illustrate that JAK2-V617F has complex effects on HSC biology.
大多数骨髓增殖性肿瘤（MPN）患者携带体细胞JAK2-V617F突变。由于其他突变可能先于JAK2-V617F出现，因此有人质疑单独的JAK2-V617F是否能引发MPN。多个小鼠模型已证明JAK2-V617F可导致MPN；然而，在所有这些模型中，疾病都是多克隆性的。相反，癌症是在单细胞水平上起始的，但迄今为止，在小鼠中重现单细胞疾病起始的尝试均告失败。我们通过有限稀释和单细胞移植证明，表现为红细胞增多症或血小板增多症的MPN疾病可以从携带JAK2-V617F的单个细胞克隆性起始。然而，只有一部分由单个造血干细胞（HSC）重建的小鼠表现出MPN表型。HSC中JAK2-V617F的表达促进细胞分裂并增加DNA损伤。在单细胞基因表达分析中，较高的JAK2-V617F表达与短期HSC特征以及增加的髓系偏向相关。祖细胞和干细胞中较低的JAK2-V617F表达与在二级受体中稳定植入的能力相关。此外，长期重建能力也存在于具有中等谱系标记表达水平的区室中。我们的研究表明，MPN可以从单个HSC起始，并表明JAK2-V617F对HSC生物学具有复杂影响。
