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Janus kinases (JAKs)

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Janus kinases (JAKs) constitute a family of intracellular, non-receptor tyrosine kinases

is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2
- are associated with their corresponding cell surface receptors and transduce signals from cytokines, as well as some hormones, such as growth hormone and prolactin
- JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions (1)
  - JAK1 seems to play a role in conditions such as:
    - pruritic dermatitis
    - allergic rhinitis
    - asthma
    - inflammatory bowel disease
  - inhibition of JAK1 and JAK2 molecules with JAK1 and JAK2 inhibitory activity have also provided therapeutic benefits in the treatment of:
    - rheumatoid arthritis
    - psoriasis
    - pruritis
  - inhibition of JAK3 several JAK3 selective inhibitors have been evaluated for their efficacy in the treatment of rheumatoid arthritis
  - TYK2 selective inhibitors may also be useful in the treatment of autoimmune diseases

JAK/STAT signaling in the pathogenesis of the myeloproliferative neoplasms (MPNs)

A central role for JAK/STAT signaling in the pathogenesis of the myeloproliferative neoplasms (MPNs) was discovered by identifying the somatically acquired JAK2V617F mutation in more than 95% of patients with polycythemia vera (PV) and over 50% of patients with essential thrombocytosis and primary myelofibrosis (2,3,4)

JAK2 V617F mutation is an acquired, somatic mutation present in the majority of patients with myeloproliferative cancer
the JAK2 V617F mutation may also be prevalent in individuals without overt signs of myeloproliferative cancer
activated JAK2 signaling by JAK2, CALR, and MPL mutations has become a focus for the development of targeted therapies for patients with MPN (3)
JAK2 inhibitors now represent a standard of clinical care for certain forms of MPN and offer important benefits for MPN patients

Reference:

Nielsen C, Birgens HS, Nordestgaard BG, Kjaer L, Bojesen SE. The JAK2 V617F somatic mutation, mortality and cancer risk in the general population. Haematologica. 2011 Mar;96(3):450-3
Bader MS, Meyer SC. JAK2 in Myeloproliferative Neoplasms: Still a Protagonist. Pharmaceuticals (Basel). 2022 Jan 28;15(2):160. doi: 10.3390/ph15020160. PMID: 35215273; PMCID: PMC8874480.
Schieber M, Crispino JD, Stein B. Myelofibrosis in 2019: moving beyond JAK2 inhibition. Blood Cancer J. 2019 Sep 11;9(9):74. doi: 10.1038/s41408-019-0236-2. PMID: 31511492; PMCID: PMC6739355.
Shawky AM, Almalki FA, Abdalla AN, Abdelazeem AH, Gouda AM. A Comprehensive Overview of Globally Approved JAK Inhibitors. Pharmaceutics. 2022 May 6;14(5):1001

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