Funakoshi-Tago Megumi
Department of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan.
Yakugaku Zasshi. 2012;132(11):1267-72. doi: 10.1248/yakushi.12-00225.
Janus kinase 2 (JAK2) is an essential non-receptor type tyrosine kinase for various cytokine signals. In 2005, a somatic JAK2 mutation (V617F) was found in the majority of myeloproliferative neoplasm (MPN) patients. It has been shown that the V617F mutation caused the constitutive activation of JAK2, exhibiting the cytokine-independent survival and proliferation of Ba/F3 cells. In addition, tumorigenesis was induced after a transplantation of Ba/F3 cells expressing JAK2 V617F mutant in nude mice, suggesting that JAK2 V617F mutant behaves as a potent oncogene product. We found that JAK2 V617F mutant causes aberrant activation of a transcription factor c-Myc, which is critical for the JAK2 V617F mutant-caused oncogenic activities. In the screening of genes which expression was induced by JAK2 V617F mutant, we detected the significant induction of target genes of c-Myc such as Aurora kinase A (Aurka) and ornithine decarboxylase (ODC). Interestingly, JAK2 V617F mutant enhanced resistance to cisplatin (CDDP)-induced DNA damage and ectopic expression of Aurka in Ba/F3 cells exhibited similar resistance to CDDP. Conversely, knockdown and inhibition of Aurka in cells expressing JAK2 V617F mutant abolished the resistance to CDDP, suggesting that Aurka is most likely critical for resistance to DNA damage in cells transformed by JAK2 V617F mutant. In addition, we found that ODC inhibitor, DL-α-difluoromethylornithine (DFMO) prevented the proliferation of the JAK2 V617F mutant-induced transformed cells. Taking these observations together, c-Myc plays an essential role in JAK2 V617F mutant-induced hematopoietic disorder and would be a good target for the treatment of MPN.
Janus激酶2（JAK2）是多种细胞因子信号传导所必需的非受体型酪氨酸激酶。2005年，在大多数骨髓增殖性肿瘤（MPN）患者中发现了一种体细胞JAK2突变（V617F）。研究表明，V617F突变导致JAK2的组成性激活，使Ba/F3细胞表现出不依赖细胞因子的存活和增殖。此外，将表达JAK2 V617F突变体的Ba/F3细胞移植到裸鼠中后可诱导肿瘤发生，这表明JAK2 V617F突变体表现为一种有效的致癌基因产物。我们发现JAK2 V617F突变体导致转录因子c-Myc的异常激活，而c-Myc对于JAK2 V617F突变体引起的致癌活性至关重要。在筛选由JAK2 V617F突变体诱导表达的基因时，我们检测到c-Myc靶基因如极光激酶A（Aurka）和鸟氨酸脱羧酶（ODC）的显著诱导。有趣的是，JAK2 V617F突变体增强了对顺铂（CDDP）诱导的DNA损伤的抗性，并且在Ba/F3细胞中异位表达Aurka表现出对CDDP的类似抗性。相反，在表达JAK2 V617F突变体的细胞中敲低和抑制Aurka消除了对CDDP的抗性，这表明Aurka很可能对于JAK2 V617F突变体转化的细胞中对DNA损伤的抗性至关重要。此外，我们发现ODC抑制剂DL-α-二氟甲基鸟氨酸（DFMO）可阻止JAK2 V617F突变体诱导的转化细胞的增殖。综合这些观察结果，c-Myc在JAK2 V617F突变体诱导的造血系统紊乱中起重要作用，并且将是治疗MPN的良好靶点。
