The polycythemia vera-associated Jak2 V617F mutant induces tumorigenesis in nude mice
The polycythemia vera-associated Jak2 V617F mutant induces tumorigenesis in nude mice
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DOI：
10.1016/j.intimp.2009.03.011
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发表时间：
2009-07-01
影响因子：
5.6
通讯作者：
Kasahara, Tadashi
中科院分区：
文献类型：
--
作者：
Abe, Miyuki;Funakoshi-Tago, Megumi;Kasahara, Tadashi
在大多数真性红细胞增多症（PV）患者中发现了体细胞Jak 2突变（V617 F）。在这里，我们表明，激活Jak 2 V617 F突变体完全保护Ba/F3细胞从细胞因子撤出诱导的凋亡性细胞死亡。有趣的是，表达Jak 2 V617 F突变体的Ba/F3细胞在裸鼠中诱导快速肿瘤发生，导致快速死亡。注射表达野生型Jak 2的Ba/F3细胞没有效果，而注射表达Jak 2 V617 F突变体的Ba/F3细胞迅速侵入并扩散到各种不同的器官，如肝脏和脾脏。引人注目的是，Jak 2抑制剂AG 490有效地抑制了由Jak 2 V617 F突变体诱导的非依赖于精氨酸的细胞生长。此外，用AG 490治疗有效地延迟了Jak 2 V617 F突变体诱导的裸鼠肿瘤发生。因此，我们的结果在体外和体内表明，Jak 2窝藏V617 F突变是一个强大的癌基因，能够促进细胞转化和肿瘤发生。(C)2009 Elsevier B. V.保留所有权利。
The somatic Jak2 mutation (V617F) was identified in most patients with polycythemia vera (PV). Here, we show that the activating Jak2 V617F mutant completely protected Ba/F3 cells from cytokine withdrawal-induced apoptotic cell death. Interestingly, Ba/F3 cells expressing Jak2 V617F mutant induced rapid tumorigenesis in nude mice, leading to rapid death. Whereas an injection of Ba/F3 cells expressing wild-type Jak2 had no effect, an injection of Ba/F3 cells expressing Jak2 V617F mutant promptly invaded and spread into various distinct organs, such as the liver and spleen. Strikingly, Jak2 inhibitor, AG490 potently inhibited cytokine-independent cell growth induced by the Jak2 V617F mutant. Also, treatment with AG490 effectively delayed Jak2 V617F mutant-induced tumorigenesis in nude mice. Thus, our results both in vitro and in vivo suggest that Jak2 harboring V617F mutation is a potent oncogene able to promote cell transformation and tumorigenesis. (C) 2009 Elsevier B.V. All rights reserved.