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.
Highlights
The non-receptor tyrosine kinase, Janus kinase 2 (JAK2), is an essential signal transducer of various cytokine signaling, including that of erythropoietin (Epo), which is required for the proliferation and differentiation of red blood cells [1,2]
We reported that constitutive activation of signal transducers and activators of transcription 5 (STAT5) induced by JAK2 (V617F) conferred growth-factor independence on Ba/F3 cells [10] and assumed that a wide range of genes induced by STAT5 activation seems to play important roles in cellular transformation induced by JAK2 (V617F); by performing DNA array analysis, the alteration of the gene expression was examined between cells expressing wild-type JAK2 with Epo receptor (EpoR) (WT/EpoR cells) and cells expressing JAK2 (V617F) with EpoR (VF/EpoR cells)
In the absence of Epo stimulation, the expression of ornithine decarboxylase (ODC) mRNA was hardly detected in EpoR cells, and this was slightly enhanced by the ectopic expression of wild-type JAK2; the expression of ODC mRNA was markedly elevated in VF/EpoR cells even to the same level as when cells were stimulated with Epo (Fig. 1B)
Summary
The non-receptor tyrosine kinase, JAK2, is an essential signal transducer of various cytokine signaling, including that of erythropoietin (Epo), which is required for the proliferation and differentiation of red blood cells [1,2]. Y114A mutation suppresses the transforming signals induced by JAK2 (V617F) These reports support the mechanism that the interaction between JAK2 (V617F) and EpoR is essential to exhibit the transforming ability of V617F mutant. We showed that an ODC inhibitor, a-difluoromethylornithine (DFMO), significantly abrogated the proliferation of transformed BaF3 cells by JAK2 (V617F) in vitro and efficiently inhibited JAK2 (V617F)-induced tumor formation in nude mice. Together, these data strongly support that ODC expression induced by c-Myc is critical for JAK2 (V617F)driven transformation and that targeted disruption of the c-MycODC axis may have therapeutic utility for the treatment of MPNs
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