Funakoshi-Tago Megumi, Tago Kenji, Sumi Kazuya, Abe Miyuki, Aizu-Yokota Eriko, Oshio Tomoyuki, Sonoda Yoshiko, Kasahara Tadashi
Department of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan.
J Biol Chem. 2009 May 8;284(19):12680-90. doi: 10.1074/jbc.M808879200. Epub 2009 Mar 16.
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.
JAK2在多种细胞过程的调节中发挥重要作用，包括细胞迁移、增殖以及抗细胞凋亡。最近，在一名急性淋巴细胞白血病患儿中发现了JAK2基因的L611S点突变。在此，我们分析了JAK2发挥致癌作用的机制。在BaF3小鼠造血细胞中，L611S突变体增加了抗凋亡蛋白的表达，包括X染色体连锁凋亡抑制蛋白、凋亡抑制蛋白和Bcl-XL。我们还发现，JAK2 L611S突变体可保护BaF3细胞免受细胞因子撤除诱导的凋亡性细胞死亡，并导致细胞因子非依赖性细胞生长。此外，表达JAK2 L611S突变体的BaF3细胞获得了在裸鼠中诱导肿瘤发生的能力。L611S突变体还表现出恶性特征，包括迅速侵袭并扩散到各个器官，导致小鼠快速死亡。最后，我们发现一种特异性JAK2抑制剂AG490，可通过诱导凋亡性细胞死亡，有效抑制JAK2 L611S突变体诱导的细胞因子非依赖性细胞生长。此外，AG490处理显著抑制了JAK2 L-611S突变体在裸鼠中诱导的肿瘤发生。因此，我们的体内外研究结果均强烈表明，JAK2的L611S突变体具有强大的致癌活性，这可能需要抗凋亡信号通路的参与。
