The Acute Lymphoblastic Leukemia-associated JAK2 L611S Mutant Induces Tumorigenesis in Nude Mice
The Acute Lymphoblastic Leukemia-associated JAK2 L611S Mutant Induces Tumorigenesis in Nude Mice
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DOI：
10.1074/jbc.m808879200
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发表时间：
2009-05-08
影响因子：
4.8
通讯作者：
Kasahara, Tadashi
中科院分区：
文献类型：
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作者：
Funakoshi-Tago, Megumi;Tago, Kenji;Kasahara, Tadashi
JAK 2在多种细胞过程的调节中起重要作用，包括细胞迁移、增殖和保护免于凋亡。最近，JAK 2的L 611 S点突变已在一名儿童急性淋巴细胞白血病中被发现。在这里，我们分析了JAK 2表现出其致瘤性的机制。在BaF 3小鼠造血细胞中，L 611 S突变体增加了抗凋亡蛋白的表达，包括X染色体连锁的凋亡抑制蛋白，凋亡抑制蛋白和Bcl-XL。我们还发现JAK 2 L 611 S突变体保护BaF 3细胞免于细胞因子撤出诱导的凋亡性细胞死亡，并导致非依赖于精氨酸的细胞生长。此外，表达JAK 2 L 611 S突变体的BaF 3细胞获得了在裸鼠中诱导成瘤的能力。L 611 S突变体也表现出恶性，包括迅速侵入和扩散到各种器官，导致小鼠迅速死亡。最后，我们发现，一个特定的JAK 2抑制剂，AG 490，有效地抑制由JAK 2 L 611 S突变体诱导的非依赖于嘌呤的细胞生长，通过诱导凋亡细胞死亡。此外，用AG 490处理显著抑制JAK 2 L 611 S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强烈表明，JAK 2的L 611 S突变体具有强大的致癌活性，这可能需要抗凋亡信号通路。
JAK2 plays important roles in the regulation of a variety of cellular processes including cell migration, proliferation, and protection from apoptosis. Recently the L611S point mutation in JAK2 has been identified in a child with acute lymphoblastic leukemia. Here we analyzed the mechanism by which JAK2 exhibits its oncogenicity. In BaF3 murine hematopoietic cells, L611S mutant increased the expression of antiapoptotic proteins including X chromosome-linked inhibitor of apoptosis protein, inhibitor of apoptosis protein, and Bcl-XL. We also showed that JAK2 L611S mutant protects BaF3 cells from cytokine withdrawal-induced apoptotic cell death and leads to cytokine-independent cell growth. Furthermore BaF3 cells expressing JAK2 L611S mutant gained the ability to induce tumorigenesis in nude mice. The L611S mutant also exhibited malignancy, including prompt invasion and spreading into various organs, leading to rapid lethality of the mice. Finally we showed that a specific JAK2 inhibitor, AG490, potently inhibited cytokine-independent cell growth induced by JAK2 L611S mutant via the induction of apoptotic cell death. In addition, treatment with AG490 significantly inhibited the JAK2 L611S mutant-induced tumorigenesis in nude mice. Thus, our results both in vitro and in vivo strongly suggest that L611S mutant of JAK2 harbors potent oncogenic activity, and this probably requires the antiapoptotic signaling pathway.