title: Critical roles of Myc-ODC axis in the cellular transformation induced by myeloproliferative neoplasm-associated JAK2 V617F mutant.
abstract: The acquired mutation (V617F) of Janus kinase 2 (JAK2) is observed in the majority of patients with myeloproliferative neoplasms (MPNs). In the screening of genes whose expression was induced by JAK2 (V617F), we found the significant induction of c-Myc mRNA expression mediated by STAT5 activation. Interestingly, GSK-3β was inactivated in transformed Ba/F3 cells by JAK2 (V617F), and this enhanced the protein expression of c-Myc. The enforced expression of c-Myc accelerated cell proliferation but failed to inhibit apoptotic cell death caused by growth factor deprivation; however, the inhibition of GSK-3β completely inhibited the apoptosis of cells expressing c-Myc. Strikingly, c-Myc T58A mutant exhibited higher proliferative activity in a growth-factor-independent manner; however, this mutant failed to induce apoptosis. In addition, knockdown of c-Myc significantly inhibited the proliferation of transformed cells by JAK2 (V617F), suggesting that c-Myc plays an important role in oncogenic activity of JAK2 (V617F). Furthermore, JAK2 (V617F) induced the expression of a target gene of c-Myc, ornithine decarboxylase (ODC), known as the rate-limiting enzyme in polyamine biosynthesis. An ODC inhibitor, difluoromethylornithine (DFMO), prevented the proliferation of transformed cells by JAK2 (V617F). Importantly, administration of DFMO effectively delayed tumor formation in nude mice inoculated with transformed cells by JAK2 (V617F), resulting in prolonged survival; therefore, ODC expression through c-Myc is a critical step for JAK2 (V617F)-induced transformation and DFMO could be used as effective therapy for MPNs.
authors.affiliation: Department of Biochemistry, Faculty of Pharmacology, Keio University, Tokyo, Japan. tago-mg@pha.keio.ac.jp
authors.forename: Megumi
authors.initials: M
authors.lastname: Funakoshi-Tago
authors.forename: Kazuya
authors.initials: K
authors.lastname: Sumi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kasahara
authors.forename: Kenji
authors.initials: K
authors.lastname: Tago
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D053938:DNA Fragmentation; D004921:Erythropoietin / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013095:Spermidine / Q000494:pharmacology
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D050799:STAT5 Transcription Factor; D004921:Erythropoietin; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D009955:Ornithine Decarboxylase; D013095:Spermidine