The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation
The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation
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DOI：
10.1073/pnas.0601462103
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发表时间：
2006-04-18
影响因子：
11.1
通讯作者：
Weissman, IL
中科院分区：
文献类型：
--
作者：
Jamieson, CHM;Gotlib, J;Weissman, IL
尽管很大一部分真性红细胞增多症（PV）患者在JAK2信号分子的617氨基酸（V617F）上存在缬氨酸到苯丙氨酸的突变，但这种突变发生的造血阶段尚不清楚。在这里，我们从16例PV患者样本和14例正常人样本中分离并表征了造血干细胞（HSC）和髓系祖细胞，测试JAK2突变是否可以在干细胞或祖细胞水平上发现，以及JAK2 v617f阳性细胞是否改变了分化潜能。在分析的所有PV样本中，与正常样本相比，具有HSC表型(CD34(+)CD38(-)CD90（+)Lin(-)）的细胞数量增加。造血祖细胞实验表明，在造血干细胞水平上，PV的分化潜能已经向红系谱系倾斜。JAK2 V617F突变可在HSC及其子代中检测到。此外，一种JAK2抑制剂AG490能有效抑制PV HSC的异常红系潜能。
Although a large proportion of patients with polycythemia vera (PV) harbor a valine-to-phenylalanine mutation at amino acid 617 (V617F) in the JAK2 signaling molecule, the stage of hematopoiesis at which the mutation arises is unknown. Here we isolated and characterized hematopoietic stem cells (HSC) and myeloid progenitors from 16 PV patient samples and 14 normal individuals, testing whether the JAK2 mutation could be found at the level of stem or progenitor cells and whether the JAK2 V617F-positive cells had altered differentiation potential. In all PV samples analyzed, there were increased numbers of cells with a HSC phenotype (CD34(+)CD38(-)CD90(+)Lin(-)) compared with normal samples. Hematopoietic progenitor assays demonstrated that the differentiation potential of PV was already skewed toward the erythroid lineage at the HSC level. The JAK2 V617F mutation was detectable within HSC and their progeny in PV. Moreover, the aberrant erythroid potential of PV HSC was potently inhibited with a JAK2 inhibitor, AG490.