JAK2

About JAK2

JAK2 on chromosome 9p24.1 encodes Janus kinase 2, a cytoplasmic tyrosine kinase that transmits signals from receptors for erythropoietin, thrombopoietin, growth hormone, and several cytokines by phosphorylating STAT transcription factors. The acquired V617F mutation in the pseudokinase domain, discovered by several groups in 2005, removes an autoinhibitory constraint and causes constitutive signaling. It is found in about 95 percent of people with polycythemia vera and in roughly half of those with essential thrombocythemia and primary myelofibrosis, the classic Philadelphia chromosome negative myeloproliferative neoplasms. Most remaining cases of the latter two carry mutations in CALR or MPL. Polycythemia vera causes increased red cell mass and thrombosis, essential thrombocythemia causes high platelet counts with thrombosis or bleeding, and myelofibrosis causes bone marrow scarring, an enlarged spleen, and low blood counts. JAK2 V617F is also found at low levels in some healthy older people as part of clonal hematopoiesis. Ruxolitinib, a JAK1 and JAK2 inhibitor, reduces spleen size and symptoms in myelofibrosis and is used in polycythemia vera, and fedratinib, pacritinib, and momelotinib are other JAK inhibitors for myelofibrosis. Related JAK inhibitors such as tofacitinib and baricitinib are used for rheumatoid arthritis and other inflammatory diseases.