see also:

• myelofibrosis
• myeloproliferative disorders
• polycythaemia rubra vera
• Janus kinase inhibitors

• Type I and II cytokine receptors are a conserved family of transmembrane proteins including the receptors for interleukins, interferons, erythropoietin, thrombopoietin, growth hormone, leptin and colony stimulating factors (CSFs)
  • functional JAK1 and JAK2 are required for embryonic development and survival
  • mutations within the JAK3 gene can present in humans as severe combined immunodeficiency syndrome (SCID) and has a devastating impact on lymphocytes
    • JAK3 is the only JAK protein capable of phosphorylating receptors carrying the γc receptor and this receptor chain is exclusively used by receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21
    • LOF mutations within the TYK2 gene are even rarer than JAK3 mutations - the few patients reported carrying the mutation show an increased susceptibility for infections, like severe infections of the skin. TYK2 LOF mutations essentially block the signal transduction of the receptors for IL-12, IL-23, and type I IFN (IFN-α/β), resulting in impaired IFN-γ+ Th1 responses and possibly IL-17+ Th17 responses.¹⁾
• these cytokine receptors lack an intrinsic kinase activity but are associated with “Janus kinases” (JAKs).
• the JAK-family consists of four members: JAK1, JAK2, JAK3 and TYK2 that have different association patterns to receptors and are part of the Signal Transducer and Activation of Transcription (JAK-STAT) pathway
• activated JAKs initiate tyrosine phosphorylation of receptors and activate corresponding STATs. The phosphorylated STATs then dimerize and enter the nucleus to regulate specific gene transcription. This process enables the rapid transmission of external signals to the nucleus to regulate biological and pathological processes.
• more than 50 types of cytokines, including interferons (IFNs), interleukins (ILs), and growth factors, have been shown to play roles in JAK-STAT signaling to fulfill regulatory functions in cell differentiation, metabolism, survival, homeostasis, and immune response ²⁾
• JAK3 and TYK2 are primarily important for immune responses
  • JAK3 associates with only one subunit, the common interleukin-2Rγ chain, or γc.
• JAK1 and JAK2 have broad functions, with roles that range from host defense and haematopoiesis to growth and neural development
  • deletion of Jak1 or Jak2 is lethal in mice
• more than 200 somatic mutations and single-nucleotide polymorphisms of JAK-STAT pathway genes have been identified that are functionally correlated with human diseases, including rheumatoid arthritis (RA), haematological malignancies, and atopic dermatitis (AD)
• abnormal hyper-activation of JAK-STAT signaling has been identified in diverse immune-mediated conditions and cancers, including melanomas, glioblastomas, and head, neck, lung, pancreatic, breast, rectal, and prostate cancers
• in 2005, an acquired mutation of the JAK2 gene (V617F mutation) was discovered in >95% of patients with polycythaemia rubra vera and in ~50% of those with essential thrombocytosis or primary myelofibrosis
  • this mutation makes Janus kinase continuously active resulting in thrombocytosis and leukocytosis (high WCC) independently from growth factor regulation.
  • does not cause myeloproliferative disease in mice lacking STAT5

• associated with:
  • interleukins 2,4,6,7,9,10,11,13,15,19,20,21,22,24,26,29
  • oncostatin M
  • leukaemia inhibitory factor
  • g-CSF
  • TNF
• gain of function mutations are associated with:
  • T and B cell ALL
  • AML
  • activated B cell-like diffuse large B cell lymphoma
• JAK1 can be activated in patients with T-cell ALL, patients with B-cell ALL who have a poor prognosis, and patients with acute myeloid leukemia

• JAK2 gene has 25 exons
• associated with:
  • interleukins 3,5,6,12,13,23
  • oncostatin M
  • leukaemia inhibitory factor
  • g-CSF
  • TNF
  • erythropoietin
  • growth hormone
  • prolactin
  • thrombopoietin
  • leptin
  • interferon gamma
• gain of function mutations are associated with:
  • polycythaemia rubra vera
  • essential thrombocytosis
  • myelofibrosis
  • Hodgkin lymphoma
  • Down syndrome-associated B cell ALL
  • primary mediastinal B cell lymphoma
• The most common alterations in JAK2 are JAK2 Mutation (2.05%), JAK2 Exon 14 Mutation (0.94%), JAK2 V617F (1.11%), JAK2 Loss (0.30%), and JAK2 Amplification (0.29%) ³⁾
• JAK2 is altered in 2.65% of all cancers with lung adenocarcinoma, myeloproliferative neoplasm, breast invasive ductal carcinoma, polycythemia vera, and colon adenocarcinoma having the greatest prevalence of alterations
• JAK2 V617F gain of function mutation:
  • this 1849G>T mutation in exon 14 results in an amino acid substitution of valine to phenylalanine (V617F) within the JH2 pseudokinase domain
  • creates a constitutively active kinase that can render hematopoietic cells independent of exogenous growth factors
  • occurs in more than 95% of patients with polycythaemia rubra vera and in 32 to 57% of patients with essential thrombocytosis or primary myelofibrosis
  • presence of a myeloproliferative neoplasm in a first-degree relative increases the risk of disease by a factor of 5 to 7
  • extended germline haplotype encompassing the JAK2 locus is responsible for much of this familial predisposition increasing the risk of disease by a factor of 3 to 4
  • even in the absence of overt myeloproliferative neoplasms (MPN), it is also associated with splanchnic vein thrombosis and in ~6% of patients with cerebral venous thrombosis (CVT) and in some patients this is recurrent independent of thrombocytosis ⁴⁾
  • studies of the JAK2 (V617F) mutation in other hematological diseases such as de novo acute myeloid leukemia, acute/chronic lymphocytic leukemia, classical Hodgkin lymphoma (cHL), primary mediastinal B cell lymphoma, follicular and mantle cell lymphoma have been negative ⁵⁾
• mutations in exon 12 of JAK2:
  • typically have an isolated erythrocytosis
• somatically acquired mutations in JAK2 have been detected in high-risk patients with B-cell acute lymphoblastic leukemia (ALL) (9%) and in patients with B-cell ALL associated with Down’s syndrome (34%), most often affecting the R683 residue

• associated with:
  • interleukins 2,4,7,9,15,21
• gain of function mutations are associated with:
  • megakaryoblastic leukaemias
• can be activated in patients with T-cell ALL, patients with adult T-cell leukemia or lymphoma, and patients with NK-cell or Τ-cell lymphoma
• mutations in the FERM domain of JAK2 gene (responsible for binding the cytoplasmic tails of cytokine receptor) have been described in 11% of patients with adult T-cell leukemia/lymphoma leading to a gain of function in JAK3 gene
• loss of function mutations are associated with:
  • severe combined immunodeficiency

• associated with:
  • interleukins 10, 12, 22, 26, 29
  • interferon alpha/beta/omega
  • interleukin-28 alpha/beta
• loss of function mutations are associated with:
  • primary immunodeficiency
• here are only two instances in which autosomal recessive mutations in TYK2 have been reported in humans resulting in:
  • child with atopic dermatitis and moderately elevated IgE levels as well as severe bacterial, viral, and fungal infections
  • other child had severe infection after vaccination with bacille Calmette–Guérin (BCG), neurobrucellosis, and infection with herpes simplex virus (HSV), but only very minor elevations in IgE levels and no atopy

• mutations may cause:
  • dominant-negative for interferon-γ signaling: children with disseminated BCG infection or nontuberculous mycobacterial infection
  • complete STAT1 deficiency blocks both interferon-γ and interferon-α signaling:
    • susceptible to viral and mycobacterial infections, which usually lead to early death
  • recessive biallelic hypomorphic mutations:
    • recurrent infections with intramacrophagic bacteria (e.g., salmonella, BCG, and nontuberculous mycobacteria) and herpes viruses (e.g., HSV, cytomegalovirus, and varicella–zoster virus), but with treatment there is adequate immunity to support survival
  • heterozygous gain-of-function or hypermorphic mutations cause chronic mucocutaneous candidiasis
    • excessive STAT1 activation causes exaggerated responses to interferon-γ and inhibits the production of interleukin-17
    • susceptible to other complications, including autoimmunity, cerebral aneurysms, and squamous-cell carcinoma
    • associated with the disseminated dimorphic yeast infections coccidioidomycosis and histoplasmosis and with the IPEX-like (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, in which the transcription factor FOXP3 and regulatory T cells are intact

• crucial for cytokines that drive the differentiation of interleukin-17–producing T cells
• critical for CD8 T-cell memory
• mediates signaling through at least six classes of receptors, making STAT3 mutations a multifaceted disease with features beyond immune-cell defects, including coronary-artery aneurysms without coronary atherosclerosis
• mutations:
  • dominant-negative mutations cause reduced interleukin-17–producing T cells and hyper-IgE syndrome which is characterized by eczema, staphylococcal boils, cyst-forming pneumonias, chronic mucocutaneous candidiasis, and extremely high levels of IgE, along with numerous nonimmunologic features, including scoliosis, fractures, characteristic facies, failure of primary tooth deciduation, and coronary-artery aneurysms
  • CD8 T-cell memory defects result in recurrent infection with varicella–zoster virus and increased circulating levels of Epstein–Barr virus

• STAT5B:
  • interleukin-2 and growth-hormone signaling
  • important for the expression of FOXP3 and interleukin-2Rα (CD25) and for the differentiation of regulatory T cells
  • down-regulates interleukin-17
  • mutations:
    • recessive STAT5B deficiency results in impaired interleukin-2 and growth-hormone signaling and immunodeficiency, autoimmunity, and growth failure
      • have severe opportunistic infections, variable lymphocyte counts, and normal-to-high levels of immunoglobulins

• act on JAK 1 and JAK 2 which then act on STAT1
• roles in mycobacterial and viral infection
• defects in STAT1 may cause chronic mucocutaneous candidiasis

• act on JAK 1 and TYK 2 which then act on STAT1 or STAT1:STAT2 system

• act on JAK 1 and JAK 3 which then act on STAT5b
• defects in STAT5b may cause dwarfism, autoimmunity states

• act on JAK 1 and JAK 2 which then act on STAT1 or STAT1:STAT2 system
• or act on JAK 1 and JAK 2 which then act on STAT3:STAT3 system
• defects may cause:
  • hyper-IgE syndrome
  • large granular lymphocytic (LGL) leukaemia
  • cancers - constitutive STAT3 or STAT5 activation is associated with many cancers

• act on JAK 1 and JAK 3 which then act on STAT5b
• defects in JAK 3 here may cause SCID
• defects in STAT5b may cause dwarfism, autoimmunity states

• act on JAK 2 which then act on STAT5a
• defects may cause cancers - constitutive STAT3 or STAT5 activation is associated with many cancers

• act on JAK 2 which then act on STAT5b
• defects in JAK 2 here may cause MF, PV, ET
• defects in STAT5b may cause dwarfism and autoimmunity syndrome

• suppressors of cytokine signaling (SOCSs)
  • The SOCS family are the major signaling molecules that attenuate the JAK-STAT pathway and include CIS, SOCS1, SOCS2, SOCS3, SOCS4, SOCS5, SOCS6, and SOCS7
  • all the SOCSs contain an SH2 domain and a SOCS cassette
  • SOCSs can be induced by cytokines such as IL-2, IL-3, and IFN-γ
  • the entry of activated STATs into the nucleus enhances the transcription of SOCSs creating a negative feedback loop
• protein inhibitors of activated STATs (PIASs)
  • the PIAS family includes PIAS1, PIAS3, PIASx, and PIASy
  • PIASs can interact with STAT to prevent STAT dimerization or prevent STAT dimers from binding to DNA
• protein tyrosine phosphatases
  • can interact with receptors to dephosphorylate JAK
  • can also directly dephosphorylate STAT dimers to inhibit JAK-STAT signaling

• source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604876/
• constitutive JAK activity due to the function of receptors that associate with JAKs which can altered by chromosomal rearrangements or mutations in cancer
  • MPL
    • activating mutations affecting the thrombopoietin receptor MPL occur in approximately 9% of patients with myelofibrosis, all of whom lack the JAK2 V617F mutation, which leads to the constitutive activation of JAK2 by the MPL receptor
  • CRLF2
    • the cytokine receptor CRLF2, which binds JAK2, is overexpressed by chromosomal rearrangements, including 50% of patients with B-cell ALL, 34% of patients with Down’s syndrome and 9% of high-risk children with B-cell ALL.
      • many leukemias with alterations in CRLF2 also have JAK2 mutations, suggesting that this receptor functions as a platform for constitutive signaling by mutant JAK2
  • 10% of patients with T-cell ALL have mutant interleukin-7 receptor α subunits, leading to constitutive JAK1 activation
  • gain-of-function mutations of the granulocyte colony-stimulating factor receptor are associated with acute myeloid leukemia in conjunction with severe congenital neutropenia
  • in-frame deletions affecting glycoprotein 130, the signaling component of the interleukin-6 receptor, are present in 60% of patients with inflammatory hepatocellular adenomas, causing JAK2 activation
• autocrine cytokine secretion activation of JAKs in several subtypes of lymphoma
  • in primary mediastinal B-cell lymphoma and Hodgkin’s lymphoma, autocrine interleukin-13 signaling activates JAK2, and in 30 to 50% of patients, its activity is further intensified by amplification of the JAK2 locus, thus, JAK2 inhibition is lethal to the cell lines for both types of lymphoma
  • autocrine secretion of interleukins 6 and 10 activates JAKs in the activated B-cell-like (ABC) subtype of diffuse large-B-cell lymphoma, promoting the survival of malignant cells
    • MY88
      • often this autocrine cytokine loop is initiated by activating mutations affecting MYD88, an adaptor protein in toll-like receptor signaling
      • the most common MYD88 mutant, termed L265P, occurs in 29% of patients with ABC diffuse large-B-cell lymphoma, and it is also present in 36% of patients with primary central nervous system lymphoma72 and 69% of patients with leg-type primary cutaneous lymphoma, both of which phenotypically resemble ABC diffuse large-B-cell lymphoma
        • STAT3 is required for the survival of ABC diffuse large-B-cell lymphoma cells
      • MYD88 L265P is also common in Waldenstrom’s macroglobulinemia (90% of cases) and occurs in a subset of marginal-zone lymphomas (10 to 11% of cases) and chronic lymphocytic leukemias (3 to 10% of cases)
• constitutive STAT activation, which is common in epithelial, liver, and breast cancers, fosters the proliferation and survival of malignant cells and tumor-promoting inflammation while mitigating antitumor immunity
• noncanonical, epigenetic roles for JAK signaling in the nucleus in leukemias and lymphomas
  • JAK2 translocates into the nucleus in leukemias with the V617F mutation and in primary mediastinal B-cell lymphoma and Hodgkin’s lymphoma with amplification of the JAK2 locus
  • JAK2 then phosphorylates the histone H3 tail on tyrosine 41, counteracting the formation of heterochromatin and promoting gene expression, including expression of the oncogene MYC in both types of lymphoma
  • the JAK2 amplicon in these lymphomas also includes JMJD2C, which encodes a chromatin modifier that counteracts the formation of heterochromatin and cooperates with JAK2 in activating genes epigenetically