Comparative Proteomic Analysis of Blood Eosinophils Reveals Redox Signaling Modifications in Patients with FIP1L1-PDGFRA-Associated Chronic Eosinophilic Leukemia
Comparative Proteomic Analysis of Blood Eosinophils Reveals Redox Signaling Modifications in Patients with FIP1L1-PDGFRA-Associated Chronic Eosinophilic Leukemia
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DOI：
10.1021/pr100836p
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发表时间：
2011-04-01
影响因子：
4.4
通讯作者：
Prin, Lionel
中科院分区：
文献类型：
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作者：
Kahn, Jean-Emmanuel;Dutoit-Lefevre, Virginie;Prin, Lionel
FIP 1 L1-PDGFRA（F/P）融合基因是高嗜酸性粒细胞综合征（HES）中的一个反复出现的分子发现，它导致融合蛋白酪氨酸激酶活性的组成性增加。尽管在动物或细胞系模型中获得了数据，但该白血病中主要嗜酸性粒细胞谱系靶向和嗜酸性粒细胞的细胞毒性的机制仍不清楚。为了更精确地确定与F/P基因相关的内在分子事件，我们进行了蛋白质组学分析，比较了F/P+嗜酸性粒细胞（F/P-Eos）和健康供体嗜酸性粒细胞（C-Eos）。使用2D-DIGE和质谱技术，我们确定了41个蛋白质显着过表达F/P-Eos和C-Eos之间。其中17.8%属于氧化还原酶家族。我们进一步观察到过氧化物氧还蛋白-2（PRX-2）的表达下调和含src-同源性-2结构域的酪氨酸磷酸酶（SHP-1）的过表达，SHP-1是调节PDGFR下游通路的酶，特别是细胞内活性氧（ROS）的产生。免疫印迹分析证实，与对照组和特发性HES患者相比，该特征似乎对F/P-Eos具有特异性。在这种可能涉及多能造血干细胞的克隆性疾病中，我们假设PDGFRA下游信号和细胞内ROS水平之间的关系可能会影响这种白血病的表型。
The FIP1L1-PDGFRA (F/P) fusion gene, which was identified as a recurrent molecular finding in hypercosinophilic syndrome (HES), lead to a constitutively increased tyrosine kinase activity of the fusion protein. Despite data obtained in animals or cell lines models, the mechanisms underlying the predominant eosinophil lineage targeting and the cytotordcity of eosinophils in this leukemia remain unclear. To define more precisely intrinsic molecular events associated with F/P gene, we performed a proteomic analysis comparing F/P+ eosinophils (F/P-Eos) and eosinophils from healthy donors (C-Eos). Using 2D-DIGE and mass spectrometry techniques, we identified 41 proteins significantly overexpressed between F/P-Eos and C-Eos. Among them, 17.8% belonged to the oxidoreductase family. We further observed a down-expression of peroxiredoxin-2 (PRX-2) and an overexpression of src-homology-2 domain containing tyrosine phosphatase (SHP-1), enzymes regulating PDGFR downstream pathways, and especially intracellular reactive oxygen species (ROS) production. This profile, confirmed in immunoblot analysis, appears specific to F/P-Eos compared to controls and patients with idiopathic HES. In this clonal disorder possibly involving a pluripotent hematopoietic stem cell, we postulate that the well documented relationships between PDGFRA downstream signals and intracellular ROS levels might influence the phenotype of this leukemia.