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Dysregulated JAK/STAT pathway is characteristic of myelofibrosis1,2

JAK/STAT pathway is chronically upregulated in all MF patients3

  • Normal JAK pathway activity is regulated by cytokine binding to the receptor4
  • The activation of JAK stimulates STAT-driven transcription of genes that increase cell proliferation and survival5
    • JAK signalling pathways control the differentiation, growth, development, and survival of immune and haematopoietic cells5
  • >90% of all MF patients have either JAK2V617F, CALR, or MPL mutations resulting in dysregulated JAK signalling6
    • Dysregulated JAK signalling leads to proliferation of haematopoietic cells and a chronic inflammatory state caused by overproduction3

MF symptoms result from cytokine-driven inflammation and overproliferation of haematopoietic stem cells in the bone marrow, both consequences of dysregulated JAK/STAT signalling7

Next: JAKAVI mechanism of action

CALR=calreticulin; JAK=Janus kinase; MF=myelofibrosis; MPL=myeloproliferative leukemia with proto-oncogene thrombopoietin receptor; STAT=signal transducers and activators of transcription protein.

References:

  1. Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117-1127.
  2. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.
  3. Verstovsek S, Almomen AK, Newberry KJ, Aleem A. Development of ruxolitinib as a myelofibrosis therapy. J Appl Hematol. 2013;4(3):89-95.
  4. Rawlings JS, Rosler KM, and Harrison DA. The JAK/STAT signaling pathway. J Cell Sci. 2004;117(8):1281-1283.
  5. Ghoreschi K, Laurence A, O'Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228(1):273-287.
  6. Tefferi A, Lasho TL, Finke CM, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014;28:(7):1472-1477. doi:10.1038/leu.2014.3.
  7. Tefferi A, Vaidya R, Caramazza D, et al. 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.