Identification of JAK2 as a mediator of FIP1L1-PDGFRA-induced eosinophil growth and function in CEL.
Identification of JAK2 as a mediator of FIP1L1-PDGFRA-induced eosinophil growth and function in CEL.
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鉴定 JAK2 作为 FIP1L1-PDGFRA 诱导的 CEL 中嗜酸性粒细胞生长和功能的介质
DOI：
10.1371/journal.pone.0034912
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Duan C
中科院分区：
文献类型：
--
作者：
Li B;Zhang G;Li C;He D;Li X;Zhang C;Tang F;Deng X;Lu J;Tang Y;Li R;Chen Z;Duan C
多能造血干细胞（HSC）中产生的Fip 1样1（FIP 1 L1）-血小板衍生生长因子受体α融合基因（F/P）导致14%至60%的患者患有嗜酸性粒细胞增多综合征（HES）。这些患者被归类为患有F/P（+）慢性嗜酸性粒细胞白血病（CEL），表现为克隆性嗜酸性粒细胞增多症，并显示出比F/P（-）HES患者更具侵袭性的疾病表型。在这种白血病中，主要的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。鉴于Janus酪氨酸激酶（JAK）/信号转导和转录激活因子（Stat）信号通路是细胞因子受体介导的嗜酸性粒细胞发育的关键，活化的Stat 3和Stat 5调节参与F/P恶性转化的基因的表达，我们研究了JAK蛋白是否以及如何参与F/P诱导的CEL的发病机制。在所有11例F/P（+）CEL患者中证实了JAK 2、Stat 3和Stat 5的F/P激活。通过JAK 2特异性短干扰RNA（siRNA）或Tryphostin衍生物AG 490（AG 490）在EOL-1、原代F/P（+）CEL细胞（PC）和T674 I F/P伊马替尼抗性细胞（IR）中体外抑制JAK 2，显著降低细胞增殖并诱导细胞凋亡。F/P可增强IL-5诱导的JAK 2活化，进一步的结果表明JAK 2抑制剂阻断了IL-5诱导的细胞迁移和体外EOL-1和PC细胞的活化。F/P-刺激JAK 2抑制细胞导致Stat 3活化显著减少，但相对正常诱导Stat 5活化。有趣的是，JAK 2抑制还以剂量依赖性方式降低PI 3 K、Akt和NF-κB活性，并抑制c-Myc和Survivin的表达水平。这些结果强烈表明，JAK 2被F/P激活，并且是F/P刺激细胞增殖和浸润所必需的，这可能是通过激活多个信号通路（包括NF-κB、Stat 3和PI 3 K/Akt）诱导c-Myc和Survivin表达来实现的。
The Fip1-like1 (FIP1L1)-platelet-derived growth factor receptor alpha fusion gene (F/P) arising in the pluripotent hematopoietic stem cell (HSC),causes 14% to 60% of patients with hypereosinophilia syndrome (HES). These patients, classified as having F/P (+) chronic eosinophilic leukemia (CEL), present with clonal eosinophilia and display a more aggressive disease phenotype than patients with F/P (–) HES patients. The mechanisms underlying predominant eosinophil lineage targeting and the cytotoxicity of eosinophils in this leukemia remain unclear. Given that the Janus tyrosine kinase (JAK)/signal transducers and activators of transcription (Stat) signaling pathway is key to cytokine receptor-mediated eosinophil development and activated Stat3 and Stat5 regulate the expression of genes involved in F/P malignant transformation, we investigated whether and how JAK proteins were involved in the pathogenesis of F/P-induced CEL. F/P activation of JAK2, Stat3 and Stat5, were confirmed in all the 11 F/P (+) CEL patients examined. In vitro inhibition of JAK2 in EOL-1, primary F/P(+) CEL cells (PC) and T674I F/P Imatinib resistant cells(IR) by either JAK2-specific short interfering RNA (siRNA) or the tryphostin derivative AG490(AG490), significantly reduced cellular proliferation and induced cellular apoptosis. The F/P can enhance the IL-5-induced JAK2 activation, and further results indicated that JAK2 inhibition blocked IL-5-induced cellular migration and activation of the EOL-1 and PC cells in vitro. F/P-stimulation of the JAK2 suppressed cells led to a significantly reduction in Stat3 activation, but relatively normal induction of Stat5 activation. Interestingly, JAK2 inhibition also reduced PI3K, Akt and NF-κB activity in a dose-dependent manner, and suppressed expression levels of c-Myc and Survivin. These results strongly suggest that JAK2 is activated by F/P and is required for F/P stimulation of cellular proliferation and infiltration, possibly through induction of c-Myc and Survivin expression via activation of multiple signaling pathways, including NF-κB, Stat3, and PI3K/Akt.
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影响因子：
11.4
作者：
Burgstaller, S.;Kreil, S.;Cross, N. C. P.
通讯作者：
Cross, N. C. P.
影响因子：
4.8
作者：
Fukushima, Kentaro;Matsumura, Itaru;Kanakura, Yuzuru
通讯作者：
Kanakura, Yuzuru
影响因子：
4.4
作者：
Kahn, Jean-Emmanuel;Dutoit-Lefevre, Virginie;Prin, Lionel
通讯作者：
Prin, Lionel
影响因子：
--
作者：
Hebenstreit, D;Horejs-Hoeck, J;Duschl, A
通讯作者：
Duschl, A
影响因子：
3.8
作者：
Lee, Ji-Sook;Yang, Eun Ju;Kim, In Sik
通讯作者：
Kim, In Sik