title: [Analysis of oncogenic signaling pathway induced by a myeloproliferative neoplasm-associated Janus kinase 2 (JAK2) V617F mutant].
abstract: 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.
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan. tago-mg@pha.keio.ac.jp
authors.forename: Megumi
authors.initials: M
authors.lastname: Funakoshi-Tago
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D064096:Aurora Kinase A / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics*; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019337:Hematologic Neoplasms / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000502:physiology*; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000201:enzymology* / Q000235:genetics*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D053614:Janus Kinase 2; D064096:Aurora Kinase A; D009955:Ornithine Decarboxylase; D002945:Cisplatin; D000518:Eflornithine