What is it about?
A number of JAK2 tyrosine kinase inhibitors have been developed as therapy for myelofibrosis, a disease usually associated with an activating mutation in the JAK2 gene (V16F). Activation of JAK2 activates the JAK-STAT pathway and leads to down stream effects such as proliferation and cytokine production. Each of the JAK2 inhibitors evaluated in this study have different kinase inhibitory properties and clinical profiles particularly in their myelosuppressive and immuno-modulatory effects. The current study was performed to provide a characterization of the differing effects of the these agents on human cells to provide a basis for understanding their differing clinical characteristics.
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Why is it important?
There is a spectrum of myeloproliferative diseases with JAK2 activation in which specific JAK2 inhibitors may convey clinical advantages over the others, either in efficacy or toxicity. For example, primary myelofibrosis may present as a highly proliferative disease with a very large spleen infiltrated with proliferating blood cells or as an inflammatory, myelodepleted disease associated with anemia and thrombocytopenia. A selective JAK2 inhibitor such as pacritinib that does not inhibit JAK1 but does suppress IRAK1 signaling has been shown to be less likely to exacerbate anemia or thrombocytopenia whereas JAK1/JAK2 inhibitors such as ruxolitinib may be more effective in treating myelofibrosis associated with a highly proliferative state.
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This page is a summary of: Comparative phenotypic profiling of the JAK2 inhibitors ruxolitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures, PLoS ONE, September 2019, PLOS,
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