Cambridge Institute for Medical Research and Department of Haematology, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK.
Cancer Cell. 2010 Nov 16;18(5):524-35. doi: 10.1016/j.ccr.2010.10.013.
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 downregulation 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.
JAK2V617F 突变与不同的骨髓增殖性肿瘤相关，包括真性红细胞增多症（PV）和原发性血小板增多症（ET），但尚不清楚它如何产生不同的疾病。通过比较个体患者的克隆衍生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 ET 和 PV 患者的 JAK2V617F 杂合性红细胞显示出不同的干扰素信号和 STAT1 磷酸化。正常 CD34阳性祖细胞中 STAT1 活性的增加产生类似于 ET 的表型，而 JAK2V617F 杂合性 ET 祖细胞中 STAT1 活性的下调则产生类似于 PV 的表型。我们的结果说明了克隆分析的力量，表明 JAK2V617F 的后果反映了 STAT5 和 STAT1 激活之间的平衡，并且与其他与信号通路突变相关的肿瘤有关。
