Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling.
Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling.
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DOI：
10.1016/j.ccr.2010.10.013
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发表时间：
2010-11-16
期刊：
影响因子：
50.3
通讯作者：
Green AR
中科院分区：
文献类型：
--
作者：
Chen E;Beer PA;Godfrey AL;Ortmann CA;Li J;Costa-Pereira AP;Ingle CE;Dermitzakis ET;Campbell PJ;Green AR
JAK2V617F突变与不同的骨髓增生性肿瘤相关，包括真性红细胞增多症（PV）和原发性血小板增多症（ET），但仍不清楚它如何产生不同的疾病。通过比较来自个体患者的克隆衍生的突变体和野生型细胞，我们证明JAK2V617F的转录后果是微妙的，并且来自ET和PV患者的JAK2V617F杂合红系细胞表现出差异干扰素信号传导和STAT1磷酸化。正常CD34阳性祖细胞中STAT1活性增加产生ET样表型，而JAK2V617F杂合ET祖细胞中STAT1活性下调产生PV样表型。我们的结果说明了克隆分析的力量，表明JAK2V617F的结果反映了STAT5和STAT1激活之间的平衡，并与其他与信号通路突变相关的肿瘤相关。
The JAK2V617F mutation is associated with distinct myeloproliferative neoplasms, including polycythemia vera (PV) and essential thrombocythemia (ET), but it remains unclear how it generates disparate disorders. By comparing clonally-derived mutant and wild-type cells from individual patients, we demonstrate that the transcriptional consequences of JAK2V617F are subtle, and that JAK2V617F-heterozygous erythroid cells from ET and PV patients exhibit differential interferon signaling and STAT1 phosphorylation. Increased STAT1 activity in normal CD34-positive progenitors produces an ET-like phenotype, whereas down-regulation of STAT1 activity in JAK2V617F-heterozygous ET progenitors produces a PV-like phenotype. Our results illustrate the power of clonal analysis, indicate that the consequences of JAK2V617F reflect a balance between STAT5 and STAT1 activation and are relevant for other neoplasms associated with signaling pathway mutations.
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作者：
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