Since the mouse models with the driver mutations of myeloproliferative neoplasms (MPNs) reproduce various pathological conditions found in MPNs patients such as blood cell increase, splenomegaly, and bone marrow fi brosis, these mouse models are extremely useful as tools to elucidate the mechanism of pathogenesis. Activation of MPL and its downstream signaling pathways is common to the JAK2, MPL, and CALR mutations, which are major driver mutations in MPNs, and is essential for the pathogenesis of MPNs. We analyzed the gene expression profi le of MPLexpressing cells in Jak2V617F transgenic mice and identified the signaling pathway responsible for bone marrow fi brosis. MPL activates the transcription factor upstream transcription factor via the p42/44 MAPK pathway, and the JAK2V617F mutant protein uses this pathway to enhance transcription of TGF-β1, a cytokine essential for bone marrow fibrosis. Inhibition of this pathway effectively suppressed organ fibrosis in Jak2V617F mice in vivo. JAK2 inhibitors have only a slow and limited effect on improving myelofibrosis. The mechanism we have discovered is a promising therapeutic target for antifi brotic therapy, which has recently been developed for patients with myelofi brosis. Such anti-fi brotic therapies may create new therapeutic benefi ts for patients with myelofi brosis that cannot be provided by JAK2 inhibitors. Since the mouse models with the driver mutations of myeloproliferative neoplasms (MPNs) reproduce various pathological conditions found in MPNs patients such as blood cell increase, splenomegaly, and bone marrow fi brosis, these mouse models are extremely useful as tools to elucidate the mechanism of pathogenesis. Activation of MPL and its downstream signaling pathways is common to the JAK2, MPL, and CALR mutations, which are major driver mutations in MPNs, and is essential for the pathogenesis of MPNs. We analyzed the gene expression profi le of MPLexpressing cells in Jak2V617F transgenic mice and identified the signaling pathway responsible for bone marrow fi brosis. MPL activates the transcription factor upstream transcription factor via the p42/44 MAPK pathway, and the JAK2V617F mutant protein uses this pathway to enhance transcription of TGF-β1, a cytokine essential for bone marrow fibrosis. Inhibition of this pathway effectively suppressed organ fibrosis in Jak2V617F mice in vivo. JAK2 inhibitors have only a slow and limited effect on improving myelofibrosis. The mechanism we have discovered is a promising therapeutic target for antifi brotic therapy, which has recently been developed for patients with myelofi brosis.
Such anti-fi brotic therapies may create new therapeutic benefi ts for patients with myelofi brosis that cannot be provided by JAK2 inhibitors.
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