Overview

Janus kinases (JAKs) are a family of nonreceptor tyrosine kinases that mediate signaling pathways involved in cell growth, survival, development, and differentiation.1


The JAK family of proteins includes JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2).


 
 

Many essential cellular events are regulated by JAK pathways.4 In myeloproliferative neoplasms (MPNs), JAK signaling activates the STAT pathway, driving disease pathogenesis.5

 

 
 

Signaling in the JAK/STAT pathway begins with the activation of JAKs by cytokines or growth factors. Activated JAKs then bind and activate the STAT transcription factors, which travel to the nucleus and bind specific regulatory DNA sequences to modulate gene transcription.1,4

 
 
 
 
 

Proper JAK/STAT signaling is essential for normal hematopoiesis and immune function.1 Dysregulation of this pathway can lead to impaired hematopoiesis, unregulated cell proliferation, inflammatory disease, and other serious consequences.4,5

 

 

 
 
 

References

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  • Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci. 2004;117(Pt 8):1281-1283.
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  • Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010;24(6):1128-1138.
  • Quintas-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: Therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115(15):3109-3117.
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  • Antonioli E, Guglielmelli P, Pancrazzi A, et al. Clinical implications of the JAK2 V617F mutation in essential thrombocythemia. Leukemia. 2005;19:1847-1849.
  • McLornan D, Percy M, McMullin MF. JAK2 V617F: A single mutation in the myeloproliferative group of disorders. Ulster Med J. 2006;75(2):112-119.
  • James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144-1148.
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  • Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: A comprehensive cytokine profiling study. J Clin Oncol. 2011;29(10):1356-1363.
  • Abdel-Wahab OI, Levine RL. Primary myelofibrosis: Update on definition, pathogenesis, and treatment. Annu Rev Med. 2009;60:233-245.
  • Scherber R, Dueck AC, Johansson P, et al. The myeloproliferative neoplasm symptom assessment form (MPN-SAF): International prospective validation and reliability trial in 402 patients. Blood. 2011;118(2):401-408.
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  • Rumi E, Pietra D, Pascutto C, et al. Clinical effect of driver mutations of JAK2, CALR or MPL in primary myelofibrosis. Blood. 2014;124:1062-1069.
  • Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-2390.
  • Rumi E, Pietra D, Guglielmelli P, et al. Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms. Blood. 2013.
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  • Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391-2405.
  • Tefferi A, Thiele J, Vannucchi AM, Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia. 2014;28(7):1407-1413.
  • Barosi G, Bergamaschi G, Marchetti M, et al. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood. 2007;110(12):4030-4036.
  • Chao MP, Gotlib J. Two faces of ET: CALR and JAK2. Blood. 2014;123(10):1438-1440.
  • Passamonti F, Rumi E, Pietra D, et al. A prospective study of 338 patients with polycythemia vera: The impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia. 2010;24(9):1574-1579.