Basic & Clinical Pharmacology & Toxicology, 2014, 114, 18–23
Doi: 10.1111/bcpt.12164
MiniReview
Therapeutic Targeting of the JAK/STAT Pathway Saara Aittom€aki1,2 and Marko Pesu1,2,3 1
Immunoregulation, Institute of Biomedical Technology, University of Tampere, Tampere, Finland, 2BioMediTech, Tampere, Finland and 3Fimlab laboratories, Pirkanmaa Hospital District, Tampere, Finland (Received 30 May 2013; Accepted 21 October 2013) Abstract: Antibodies that block cytokine function provide a powerful therapeutic tool especially for the treatment of autoimmune diseases. Cytokines are a group of small hydrophilic glycoproteins that bind their receptors on the cell surface and subsequently activate intracellular signalling cascades, such as the JAK/STAT pathway. A bulk of evidence has demonstrated that genetic mutations in signalling molecules can cause immunodeficiencies and malignant cell growth. As a result, several drug companies have begun to develop therapeutics that inhibit the function of JAK tyrosine kinases. Currently, two JAK inhibitors, tofacitinib and ruxolitinib, are used in the clinic for treating rheumatoid arthritis and myeloproliferative diseases, respectively. Inhibiting JAK function has been shown to efficiently prevent the uncontrolled growth of cancerous cells and to harness overly active immune cells. In the future, other small molecule compounds are likely to come into clinical use, and intense work is ongoing to develop inhibitors that specifically target the constitutively active mutant JAKs. This MiniReview will summarize the basic features of the JAK/STAT pathway, its role in human disease and the therapeutic potential of JAK/STAT inhibitors.
The JAK/STAT Pathway Cytokines are a large family of secreted proteins that play important roles in the regulation of cell growth and differentiation as well as in all aspects of the immune response. A major subgroup of cytokines exert their effects via binding to and activating a family of conserved receptors, type I and II cytokine receptors. This subfamily of cytokines consists of over 50 members in mammals and includes interferons, colonystimulating factors and many interleukins (reviewed in: [1,2]). Some hormones such as prolactin, growth hormone and erythropoietin also signal via type I cytokine receptors. The signal is transduced through a common pathway, the JAK/STAT pathway, discovered roughly 20 years ago (fig. 1) (reviewed in [3]). JAKs or Janus kinases are a family of four tyrosine kinases (JAK1, JAK2, JAK3 and TYK2) that selectively associate with cytokine receptor chains and mediate signalling by phosphorylating tyrosine residues on various proteins in the pathway, including themselves and the receptor chains, and STAT (signal transducer and activator of transcription) transcription factors [4]. STATs bind to the phosphorylated tyrosine residues on the receptor, and after phosphorylation by JAKs, STATs dimerize and translocate to the nucleus, where they bind to DNA and can either activate or repress transcription [5]. There are seven members of the STAT family in mammals: STAT1, STAT2, STAT3, STAT4, STAT5A, Author for correspondence: Marko Pesu, Institute of Biomedical Technology, University of Tampere, FinnMedi 2, 5th floor, Biokatu 8, Tampere FI-33520, Finland (fax: +358 3 364 1291, e-mail: [email protected]).
STAT5B and STAT6. Although they can be activated by partially overlapping sets of cytokines, different STAT molecules have non-redundant biological roles [6,7]. For example, STAT1 and STAT2 mediate interferon signalling, whereas STAT4 functions in IL-12 signalling and is thus instrumental for the differentiation of T helper (Th) 1 cells. STAT6 is responsible for IL-4 and IL-13 signalling, and this way it mediates IgE-dependent allergic reactions [8]. STAT3 and STAT5A/B are responsive to a broader range of cytokines, shown by the lethal phenotypes of mice deficient in either STAT3 or STAT5A and STAT5B [9]. JAKs are large tyrosine kinases. They are more than a thousand amino acids in length and have molecular masses ranging from 110 to 140 kDa [10]. All the four members of the JAK family have a similar structure and are composed of an N-terminal FERM (a band four point one, ezrin, radixin, moesin) domain, an SH2-like domain, a JH2 domain and a C-terminal JH1 domain [11]. The FERM domain is involved in the association of the JAKs with the receptor chains as well as in the autoregulation of JAKs, as is demonstrated by gain-of-function mutations of the JAK3 FERM domain in patients with T-cell leukaemia/lymphoma [12]. The role of the SH2-like domain is currently unclear but it does not seem to function as a conventional phosphotyrosine-binding domain. JH1 possesses a kinase activity and is activated by transphosphorylation of the tandem tyrosines located in its activation loop, mediated by other receptor complex-associated JAK molecules. JH2, also called the pseudokinase domain, regulates JH1 in ways that are at present poorly understood at the molecular level. JAK2 JH2 was previously thought to be catalytically inactive, but
© 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd
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TARGETING THE JAK-STAT PATHWAY
A
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B
Fig. 1. JAK inhibitors can be used in both immunosuppression (A) and to suppress hematopoiesis (B). Shown here are three cytokines and their cognate receptor complexes with the associated JAKs. IL-2 and EPO receptor activation predominantly recruits STAT5, whereas IFNc receptor activation mainly results in STAT1 recruitment. The recruited STATs are activated via phosphorylation by the associated JAKs, after which they dimerize and translocate to the nucleus where they regulate transcription.
recent work by Silvennoinen and colleagues shows that JAK2 JH2 has a protein kinase fold structure and that it is able to phosphorylate two residues in JAK2, Ser523 and Tyr570, which negatively regulate JH1 activity [13,14]. JH2 may also have a positive regulatory function, because some mutations in JAK3 JH2 cause severe combined immunodeficiency due to loss of function [15]. Receptor complexes associate with different JAK proteins. For example, the erythropoietin receptor has two identical subunits that dimerize upon ligand binding and thus bring the two associated JAK2 molecules into close proximity to be transphosphorylated by each other [16]. TYK2, on the other hand, is always associated with heteromeric receptor complexes and interacts with JAK1 or JAK2 [10]. The roles of the different JAKs in heteromeric receptor signalling are incompletely understood, for example, if they are equally required in downstream signalling [17]. The JAK/STAT Pathway in Human Disease In addition to its important role in human physiology, the erratic function of the JAK/STAT pathway in disease has received increasing attention in recent years. Defects in the pathway often result from genetic mutations that inactivate a JAK/STAT molecule. Alternatively, mutations in the JAK structure can also give rise to a kinase that is constitutively active.
Genetic inactivation of JAK1 [18] and JAK2 [19] in mice results in lethal phenotypes, which are due to an ill-defined neurological disorder in JAK1 knock-out mice and the lack of correct erythropoiesis in JAK2 knock-out mice. Therefore, it is not surprising that completely inactive forms of these kinases have not been identified in human beings. In contrast, the main function of JAK3 and TYK2 is the regulation of the immune system, and mice with inactive alleles survive but have a defective immune system [20,21]. Accordingly, several inactivating point mutations in the human Jak3 gene have been shown to cause severe combined immunodeficiency (SCID) due to the absence of common gamma chain – family cytokine signalling. Patients are characterized by severely reduced T and NK cell numbers and impaired B-cell function, but apparent defects in other organs have not been reported [22,23]. The role of TYK2 mutations in human disease is more complex; two separate findings demonstrate that autosomal recessive TYK2 mutations can result in atopic dermatitis, elevated IgE and bacterial/viral infections; also severe infections after vaccination have been reported [24,25]. The aforementioned findings in both animal models and patients prompted researchers to consider specific JAK3 inhibitors as well-tolerated and effective immunosuppressants. The roles of overly active JAK kinases have become evident in myeloproliferative diseases and hematological cancers. For example, the V617F mutation in the JAK2 pseudokinase
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domain disrupts its autoinhibitory function and results in the constant activation of JAK2/STAT5 signalling and accelerated hematopoiesis [26]. The V617F mutation is acquired, and it occurs in more than 95% of patients with polycythaemia vera and in 32% to 57% of patients with essential thrombocythaemia or primary myelofibrosis [27–29]. Gain-of-function mutations in all but TYK2 kinase have been linked with leukaemias; mutation-based JAK1, JAK2 and JAK3 hyperactivity has been identified in patients with acute T-cell lymphocytic leukaemia, acute B-cell lymphocytic leukaemia, acute myeloid leukaemia and lymphomas, for example [6]. These findings imply that inhibitors that could specifically target the mutated kinase would be particularly beneficial in the treatment for these diseases. Some of the STAT transcription factor genes have also been reported to possess loss and gain-of-function mutations. Inactivating mutations in the STAT1 and STAT5B genes result in the disruption of cytokine signalling by interferons and other immunoregulatory cytokines, and carriers suffer from infections and even immunodeficiencies [6]. STAT5B also mediates growth hormone signalling, and consequently, inactive STAT5B associates with growth retardation [30]. Recent discoveries in the Th17 cell subtype identified STAT3 as the critical factor for immunity against certain bacteria and fungi; patients with loss-of-function alleles of STAT3 have Job’s syndrome (alternatively hyper-IgE syndrome), which is characterized by high levels of IgE, staphylococcal boils and chronic candidiasis. However, patients also have non-immunological problems, such as fractures and scoliosis [31,32]. Similarly to the hyper-active mutant JAKs, gain-of-function mutations in STAT3 and 5 are seen in multiple cancers, including leukaemias and lymphomas [6,33,34]. Finally, polymorphisms in the regulatory regions of STAT genes have been linked with multiple immunological diseases. For example, the SNP rs7574865 in the STAT4 intron strongly associates with multiple autoimmune diseases via an as yet unidentified mechanism [35,36]. It is noteworthy that unlike the JAK kinases, the STAT transcription factors do not possess enzymatic activity, which makes their therapeutic targeting difficult. However, small molecule inhibitors that target STAT dimerization, oligonucleotides that prevent DNA-binding and small interfering RNAs that block STAT expression have been tested in experimental settings with variable success [37]. JAK Inhibitors The concept of interfering with JAK kinase activity in human disease stems from two different observations. Firstly, JAKs mediate the signalling of multiple immunomodulatory cytokines, and therefore, inhibiting normal JAK function can result in immunosuppression. It has been of particular interest to design inhibitors against JAK3, because both JAK3-deficient animals and patients carrying inactive alleles display a phenotype that is restricted to the immune system [38]. In addition, the identification of carriers of the gain-of-function mutant JAK in myeloproliferative diseases and cancer has resulted in the development of small chemical compounds for the treatment
MiniReview
of malignancies. At present, two JAK inhibitors have received FDA approval for clinical use. Ruxolitinib (INCB018424, Jakafi, Incyte) is a potent inhibitor of both JAK1 and JAK2, and it received FDA approval in November 2011 for the treatment of polycythaemia vera and myelofibrosis [39,40]. Currently, ruxolitinib is approved for clinical use in 36 countries. Although the JAK2V617F mutant is the culprit in these diseases, ruxolitinib has a similar inhibitory effect on both wild-type and mutant JAK2. The adverse effects arise mainly from the lack of selectivity towards the mutant JAK2; patients who have been treated with ruxolitinib have been reported to have dose-dependent neutropenia and thrombocytopenia along with more general side effects such as fatigue, nausea and headache [41]. Importantly, adjusting the drug dosage can alleviate the leucopenia, and it is also noteworthy that ruxolitinib can be administered per orally (5–25 mg BID); therefore, patients are not required to visit the hospital for drug administration. The efficacy of ruxolitinib treatment was convincingly demonstrated in several randomized, placebo-controlled, multi-centre trials. Roughly half of the patients with myeloproliferative disorder benefitted from the treatment within the first 3 months as demonstrated by more than a 50% reduction in spleen size and systemic symptoms and improved survival. Due to the central role of JAK1 and JAK2 in the regulation of immune responses, ruxolitinib has also been studied in the treatment for autoimmune diseases [42]. Preliminary results demonstrate both efficacy and safety in a phase IIa trial in patients with rheumatoid arthritis [43]. Tofacitinib (CP690, 550, Xeljanz; Pfizer) was initially designed to be a specific inhibitor of JAK3 kinase and therefore intended primarily to be used as an immunosuppressant in transplantations and for the treatment of autoimmune diseases [44]. As mentioned above, it was expected that the specific blocking of JAK3 would result in the efficient harnessing of an overly active adaptive immunity while having minimal non-immunological side effects. More recently, it was found that tofacitinib also inhibits the kinase activity of the JAK1 enzyme but has little effect on JAK2 or TYK2 function [45,46]. However, inhibiting JAK1 is beneficial in immunosuppression; JAK1 mediates, for example, interferon and IL-6 signalling, which are the key pro-inflammatory cytokines in innate immunity [42]. Similarly to ruxolitinib, tofacitinib can also be administered per orally, and it received FDA approval for the treatment of moderately to severely active rheumatoid arthritis in November 2012 [47]. In contrast, the European Medicines Agency found the overall safety profile of Xeljanz to be inacceptable and accordingly has refused Pfizer’s application for clinical use in April 2013. Tofacitinib can be used as a monotherapy or in combination with methotrexate and/or other non-biological disease modifying antirheumatic drugs (DMARDs). There are also several ongoing clinical trials that test the usefulness of tofacitinib as an immunosuppressive agent in transplantations and in the treatment for other autoimmune diseases, such as psoriasis and colitis [42]. The adverse effects include infections, hyperlipidaemia and GI track dysfunction. Therefore, serum lipids and blood cell counts need to be monitored during the treatment.
© 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd
MiniReview
TARGETING THE JAK-STAT PATHWAY
The emerging new JAK inhibitors from several drug companies are also mainly intended to be used as either immunosuppressive agents or in harnessing uncontrolled cell growth in malignancies (table 1). For example, baricitinib, another JAK1/2 inhibitor both and a specific JAK3 blocker VX-509 have all demonstrated their efficacy in the treatment for arthritis [42]. There have also been at least ten phase I/II clinical trials that assess novel JAK inhibitors, such as CEP701, SB1518, CYT387, SAR302503, AZD1480 and L019 in the treatment for myeloproliferative disorders [41]. Therefore, it is plausible that we will see more JAK inhibitors in the clinic in the coming years.
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Concluding Remarks Since its discovery in the early 1990s, the JAK/STAT pathway has been under intense investigation. More than two decades of hard work was required before the approval of the first therapeutic agents that target this signalling route. In the near future, we can expect to see the launch of more compounds that target JAK kinase activity. It will be interesting to see whether the next generation of these drugs will be able to block the function of mutated JAKs, but leave the wild-type kinase unaffected. This approach has recently become more feasible; the gain-of-function mutations in myeloproliferative
Table 1. Clinical trials of JAK inhibitors. Inhibitor
JAKs affected
Ruxolitinib
JAK1, JAK2
INCB018424 Phosphate cream Tofacitinib
JAK1, JAK2
Lestaurtinib
JAK2
Baricitinib
JAK1, JAK2
SB1518 (Pacritinib)
JAK2
CYT387 SAR302503
JAK1, JAK2 JAK1, JAK2
XL019
JAK1, JAK2
VX-509 AZD1480
JAK3 JAK1, JAK2
INCB16562
JAK1, JAK2
NVP-BSK805 GLPG0634 R-348
JAK2 JAK1, JAK2, TYK2 JAK3
JAK1, JAK3
Indication
Phase
Myelofibrosis Polycythaemia vera Acute leukaemia, lymphoma Multiple myeloma Essential thrombocythaemia Prostate cancer Breast cancer Pancreatic cancer Rheumatoid arthritis Psoriasis
FDA approved FDA approved II I-II II II II II II II
Rheumatoid arthritis Ulcerative colitis Psoriasis Renal transplantation Juvenile idiopathic arthritis Dry eyes Polycythaemia vera Essential thrombocythaemia Myelofibrosis Multiple myeloma Acute leukaemia, lymphoma Neuroblastoma Psoriasis Rheumatoid arthritis Psoriasis Diabetic nephropathy Myelofibrosis Lymphoma Myelofibrosis Myelofibrosis Polycythaemia vera, essential thrombocythaemia Solid tumours Myelofibrosis Polycythaemia vera Rheumatoid arthritis Myelofibrosis Post-polycythaemia vera/essential thrombocythaemia Solid tumours Myelofibrosis Multiple myeloma Polycythaemia vera Rheumatoid arthritis Rheumatoid arthritis Dry eyes
FDA approved III III II I II I/II I/II I/II II II I II II II II I/II I/II I/II I/II II I Discontinued (high Rate of neurotoxicity) II I/II I/II I Pre-clinical Pre-clinical Pre-clinical II I I
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diseases and cancers are often in the JAK pseudokinase domain, which is now known to possess kinase activity [13]. This finding makes it a more viable target for drug design. Specific inhibition would reduce unwarranted side effects and therefore also improve the efficacy of the treatment. Also, despite several experimental attempts, we are still far from being able to provide specific and efficient STAT inhibitors for clinical use. Targeting transcription factors is not trivial, but it would enable a more specific blocking of, for example, atopic (STAT6 inhibition) or cell-mediated inflammation (STAT4 inhibition). Acknowledgements This work was financially supported by the Academy of Finland (projects 128623, 135980), a Marie Curie International Reintegration Grant within the 7th European Community Framework Programme, the Emil Aaltonen Foundation, the Sigrid Juselius Foundation, the Tampere Tuberculosis Foundation and Competitive Research Funding of the Tampere University Hospital (Grants 9M080, 9N056). Competing Financial Interests None. References 1 O’Shea JJ, Gadina M, Kanno Y. Cytokine signaling: birth of a pathway. J Immunol 2011;187:5475–8. 2 Ihle JN. Cytokine receptor signalling. Nature 1995;377:591–4. 3 Stark GR, Darnell JE Jr. The JAK-STAT pathway at twenty. Immunity 2012;36:503–14. 4 Laurence A, Pesu M, Silvennoinen O, O’Shea J. JAK kinases in health and disease: an update. Open Rheumatol J 2012;6:232–44. 5 Vahedi G, Takahashi H, Nakayamada S, Sun HW, Sartorelli V, Kanno Y, et al. STATs shape the active enhancer landscape of T cell populations. Cell 2012;151:981–93. 6 O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 2013;368:161–70. 7 O’Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 2012;36:542–50. 8 Kaplan MH, Grusby MJ. Regulation of T helper cell differentiation by STAT molecules. J Leukoc Biol 1998;64:2–5. 9 Leonard WJ, O’Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol 1998;16:293–322. 10 Yamaoka K, Saharinen P, Pesu M, Holt VE 3rd, Silvennoinen O, O’Shea JJ. The janus kinases (jaks). Genome Biol 2004;5:253. 11 Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O’Shea JJ. Therapeutic targeting of janus kinases. Immunol Rev 2008;223: 132–42. 12 Pesu M. Mutant JAK3 FERMents ATLL. Blood 2011;118:3759–60. 13 Ungureanu D, Wu J, Pekkala T, Niranjan Y, Young C, Jensen ON, et al. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat Struct Mol Biol 2011;18:971–6. 14 Bandaranayake RM, Ungureanu D, Shan Y, Shaw DE, Silvennoinen O, Hubbard SR. Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F. Nat Struct Mol Biol 2012;19:754–9. 15 Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman MJ, et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 1995;270:797–800.
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16 Yoshimura A, Misawa H. Physiology and function of the erythropoietin receptor. Curr Opin Hematol 1998;5:171–6. 17 Li Z, Gakovic M, Ragimbeau J, Eloranta ML, Ronnblom L, Michel F, et al. Two rare disease-associated Tyk2 variants are catalytically impaired but signaling competent. J Immunol 2013;190: 2335–44. 18 Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, et al. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the jaks in cytokine-induced biologic responses. Cell 1998;93:373–83. 19 Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998;93:397–409. 20 Thomis DC, Gurniak CB, Tivol E, Sharpe AH, Berg LJ. Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 1995;270:794–7. 21 Karaghiosoff M, Neubauer H, Lassnig C, Kovarik P, Schindler H, Pircher H, et al. Partial impairment of cytokine responses in Tyk2deficient mice. Immunity 2000;13:549–60. 22 Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, et al. Mutations of jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 1995;377:65–8. 23 Pesu M, Candotti F, Husa M, Hofmann SR, Notarangelo LD, O’Shea JJ. Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs. Immunol Rev 2005;203: 127–42. 24 Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 2006;25:745–55. 25 Kilic SS, Hacimustafaoglu M, Boisson-Dupuis S, Kreins AY, Grant AV, Abel L, et al. A patient with tyrosine kinase 2 deficiency without hyper-IgE syndrome. J Pediatr 2012;160:1055–7. 26 Pesu M, O’Shea J, Hennighausen L, Silvennoinen O. Identification of an acquired mutation in Jak2 provides molecular insights into the pathogenesis of myeloproliferative disorders. Mol Interv 2005;5:211–5. 27 Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054–61. 28 Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779–90. 29 James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144–8. 30 Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med 2003;349:1139–47. 31 Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 2008;452:773–6. 32 Siegel AM, Heimall J, Freeman AF, Hsu AP, Brittain E, Brenchley JM, et al. A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. Immunity 2011;35:806–18. 33 Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmaki H, Andersson EI, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med 2012;366:1905–13. 34 Rajala HL, Eldfors S, Kuusanmaki H, van Adrichem AJ, Olson T, Lagstrom S, et al. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood 2013;121:4541–50. 35 Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007;357:977–86.
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36 Korman BD, Kastner DL, Gregersen PK, Remmers EF. STAT4: genetics, mechanisms, and implications for autoimmunity. Curr Allergy Asthma Rep 2008;8:398–403. 37 Wang BX, Platanias LC, Fish EN. STAT activation in malignancies: roles in tumor progression and in the generation of antineoplastic effects of IFNs. J Interferon Cytokine Res 2013;33: 181–8. 38 O’Shea JJ, Pesu M, Borie DC, Changelian PS. A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat Rev Drug Discov 2004;3:555–64. 39 Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, CortesFranco J, Thomas DA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 2010;363:1117–27. 40 Internet. http://www.jakafi.com (last accessed on October 2013). 41 Sonbol MB, Firwana B, Zarzour A, Morad M, Rana V, Tiu RV. Comprehensive review of JAK inhibitors in myeloproliferative neoplasms. Ther Adv Hematol 2013;4:15–35.
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42 O’Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis 2013;72 (Suppl 2):ii111–5. 43 Quintas-Cardama A, Kantarjian H, Cortes J, Verstovsek S. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov 2011;10:127–40. 44 Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin WH, et al. Prevention of organ allograft rejection by a specific janus kinase 3 inhibitor. Science 2003;302:875–8. 45 Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 2008;26:127–32. 46 Meyer DM, Jesson MI, Li X, Elrick MM, Funckes-Shippy CL, Warner JD, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond) 2010;7:41. 47 Internet. http://www.xeljanz.com (last accessed on October 2013).
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Doi: 10.1111/bcpt.12164
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Therapeutic Targeting of the JAK/STAT Pathway Saara Aittom€aki1,2 and Marko Pesu1,2,3 1
Immunoregulation, Institute of Biomedical Technology, University of Tampere, Tampere, Finland, 2BioMediTech, Tampere, Finland and 3Fimlab laboratories, Pirkanmaa Hospital District, Tampere, Finland (Received 30 May 2013; Accepted 21 October 2013) Abstract: Antibodies that block cytokine function provide a powerful therapeutic tool especially for the treatment of autoimmune diseases. Cytokines are a group of small hydrophilic glycoproteins that bind their receptors on the cell surface and subsequently activate intracellular signalling cascades, such as the JAK/STAT pathway. A bulk of evidence has demonstrated that genetic mutations in signalling molecules can cause immunodeficiencies and malignant cell growth. As a result, several drug companies have begun to develop therapeutics that inhibit the function of JAK tyrosine kinases. Currently, two JAK inhibitors, tofacitinib and ruxolitinib, are used in the clinic for treating rheumatoid arthritis and myeloproliferative diseases, respectively. Inhibiting JAK function has been shown to efficiently prevent the uncontrolled growth of cancerous cells and to harness overly active immune cells. In the future, other small molecule compounds are likely to come into clinical use, and intense work is ongoing to develop inhibitors that specifically target the constitutively active mutant JAKs. This MiniReview will summarize the basic features of the JAK/STAT pathway, its role in human disease and the therapeutic potential of JAK/STAT inhibitors.
The JAK/STAT Pathway Cytokines are a large family of secreted proteins that play important roles in the regulation of cell growth and differentiation as well as in all aspects of the immune response. A major subgroup of cytokines exert their effects via binding to and activating a family of conserved receptors, type I and II cytokine receptors. This subfamily of cytokines consists of over 50 members in mammals and includes interferons, colonystimulating factors and many interleukins (reviewed in: [1,2]). Some hormones such as prolactin, growth hormone and erythropoietin also signal via type I cytokine receptors. The signal is transduced through a common pathway, the JAK/STAT pathway, discovered roughly 20 years ago (fig. 1) (reviewed in [3]). JAKs or Janus kinases are a family of four tyrosine kinases (JAK1, JAK2, JAK3 and TYK2) that selectively associate with cytokine receptor chains and mediate signalling by phosphorylating tyrosine residues on various proteins in the pathway, including themselves and the receptor chains, and STAT (signal transducer and activator of transcription) transcription factors [4]. STATs bind to the phosphorylated tyrosine residues on the receptor, and after phosphorylation by JAKs, STATs dimerize and translocate to the nucleus, where they bind to DNA and can either activate or repress transcription [5]. There are seven members of the STAT family in mammals: STAT1, STAT2, STAT3, STAT4, STAT5A, Author for correspondence: Marko Pesu, Institute of Biomedical Technology, University of Tampere, FinnMedi 2, 5th floor, Biokatu 8, Tampere FI-33520, Finland (fax: +358 3 364 1291, e-mail: [email protected]).
STAT5B and STAT6. Although they can be activated by partially overlapping sets of cytokines, different STAT molecules have non-redundant biological roles [6,7]. For example, STAT1 and STAT2 mediate interferon signalling, whereas STAT4 functions in IL-12 signalling and is thus instrumental for the differentiation of T helper (Th) 1 cells. STAT6 is responsible for IL-4 and IL-13 signalling, and this way it mediates IgE-dependent allergic reactions [8]. STAT3 and STAT5A/B are responsive to a broader range of cytokines, shown by the lethal phenotypes of mice deficient in either STAT3 or STAT5A and STAT5B [9]. JAKs are large tyrosine kinases. They are more than a thousand amino acids in length and have molecular masses ranging from 110 to 140 kDa [10]. All the four members of the JAK family have a similar structure and are composed of an N-terminal FERM (a band four point one, ezrin, radixin, moesin) domain, an SH2-like domain, a JH2 domain and a C-terminal JH1 domain [11]. The FERM domain is involved in the association of the JAKs with the receptor chains as well as in the autoregulation of JAKs, as is demonstrated by gain-of-function mutations of the JAK3 FERM domain in patients with T-cell leukaemia/lymphoma [12]. The role of the SH2-like domain is currently unclear but it does not seem to function as a conventional phosphotyrosine-binding domain. JH1 possesses a kinase activity and is activated by transphosphorylation of the tandem tyrosines located in its activation loop, mediated by other receptor complex-associated JAK molecules. JH2, also called the pseudokinase domain, regulates JH1 in ways that are at present poorly understood at the molecular level. JAK2 JH2 was previously thought to be catalytically inactive, but
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TARGETING THE JAK-STAT PATHWAY
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B
Fig. 1. JAK inhibitors can be used in both immunosuppression (A) and to suppress hematopoiesis (B). Shown here are three cytokines and their cognate receptor complexes with the associated JAKs. IL-2 and EPO receptor activation predominantly recruits STAT5, whereas IFNc receptor activation mainly results in STAT1 recruitment. The recruited STATs are activated via phosphorylation by the associated JAKs, after which they dimerize and translocate to the nucleus where they regulate transcription.
recent work by Silvennoinen and colleagues shows that JAK2 JH2 has a protein kinase fold structure and that it is able to phosphorylate two residues in JAK2, Ser523 and Tyr570, which negatively regulate JH1 activity [13,14]. JH2 may also have a positive regulatory function, because some mutations in JAK3 JH2 cause severe combined immunodeficiency due to loss of function [15]. Receptor complexes associate with different JAK proteins. For example, the erythropoietin receptor has two identical subunits that dimerize upon ligand binding and thus bring the two associated JAK2 molecules into close proximity to be transphosphorylated by each other [16]. TYK2, on the other hand, is always associated with heteromeric receptor complexes and interacts with JAK1 or JAK2 [10]. The roles of the different JAKs in heteromeric receptor signalling are incompletely understood, for example, if they are equally required in downstream signalling [17]. The JAK/STAT Pathway in Human Disease In addition to its important role in human physiology, the erratic function of the JAK/STAT pathway in disease has received increasing attention in recent years. Defects in the pathway often result from genetic mutations that inactivate a JAK/STAT molecule. Alternatively, mutations in the JAK structure can also give rise to a kinase that is constitutively active.
Genetic inactivation of JAK1 [18] and JAK2 [19] in mice results in lethal phenotypes, which are due to an ill-defined neurological disorder in JAK1 knock-out mice and the lack of correct erythropoiesis in JAK2 knock-out mice. Therefore, it is not surprising that completely inactive forms of these kinases have not been identified in human beings. In contrast, the main function of JAK3 and TYK2 is the regulation of the immune system, and mice with inactive alleles survive but have a defective immune system [20,21]. Accordingly, several inactivating point mutations in the human Jak3 gene have been shown to cause severe combined immunodeficiency (SCID) due to the absence of common gamma chain – family cytokine signalling. Patients are characterized by severely reduced T and NK cell numbers and impaired B-cell function, but apparent defects in other organs have not been reported [22,23]. The role of TYK2 mutations in human disease is more complex; two separate findings demonstrate that autosomal recessive TYK2 mutations can result in atopic dermatitis, elevated IgE and bacterial/viral infections; also severe infections after vaccination have been reported [24,25]. The aforementioned findings in both animal models and patients prompted researchers to consider specific JAK3 inhibitors as well-tolerated and effective immunosuppressants. The roles of overly active JAK kinases have become evident in myeloproliferative diseases and hematological cancers. For example, the V617F mutation in the JAK2 pseudokinase
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domain disrupts its autoinhibitory function and results in the constant activation of JAK2/STAT5 signalling and accelerated hematopoiesis [26]. The V617F mutation is acquired, and it occurs in more than 95% of patients with polycythaemia vera and in 32% to 57% of patients with essential thrombocythaemia or primary myelofibrosis [27–29]. Gain-of-function mutations in all but TYK2 kinase have been linked with leukaemias; mutation-based JAK1, JAK2 and JAK3 hyperactivity has been identified in patients with acute T-cell lymphocytic leukaemia, acute B-cell lymphocytic leukaemia, acute myeloid leukaemia and lymphomas, for example [6]. These findings imply that inhibitors that could specifically target the mutated kinase would be particularly beneficial in the treatment for these diseases. Some of the STAT transcription factor genes have also been reported to possess loss and gain-of-function mutations. Inactivating mutations in the STAT1 and STAT5B genes result in the disruption of cytokine signalling by interferons and other immunoregulatory cytokines, and carriers suffer from infections and even immunodeficiencies [6]. STAT5B also mediates growth hormone signalling, and consequently, inactive STAT5B associates with growth retardation [30]. Recent discoveries in the Th17 cell subtype identified STAT3 as the critical factor for immunity against certain bacteria and fungi; patients with loss-of-function alleles of STAT3 have Job’s syndrome (alternatively hyper-IgE syndrome), which is characterized by high levels of IgE, staphylococcal boils and chronic candidiasis. However, patients also have non-immunological problems, such as fractures and scoliosis [31,32]. Similarly to the hyper-active mutant JAKs, gain-of-function mutations in STAT3 and 5 are seen in multiple cancers, including leukaemias and lymphomas [6,33,34]. Finally, polymorphisms in the regulatory regions of STAT genes have been linked with multiple immunological diseases. For example, the SNP rs7574865 in the STAT4 intron strongly associates with multiple autoimmune diseases via an as yet unidentified mechanism [35,36]. It is noteworthy that unlike the JAK kinases, the STAT transcription factors do not possess enzymatic activity, which makes their therapeutic targeting difficult. However, small molecule inhibitors that target STAT dimerization, oligonucleotides that prevent DNA-binding and small interfering RNAs that block STAT expression have been tested in experimental settings with variable success [37]. JAK Inhibitors The concept of interfering with JAK kinase activity in human disease stems from two different observations. Firstly, JAKs mediate the signalling of multiple immunomodulatory cytokines, and therefore, inhibiting normal JAK function can result in immunosuppression. It has been of particular interest to design inhibitors against JAK3, because both JAK3-deficient animals and patients carrying inactive alleles display a phenotype that is restricted to the immune system [38]. In addition, the identification of carriers of the gain-of-function mutant JAK in myeloproliferative diseases and cancer has resulted in the development of small chemical compounds for the treatment
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of malignancies. At present, two JAK inhibitors have received FDA approval for clinical use. Ruxolitinib (INCB018424, Jakafi, Incyte) is a potent inhibitor of both JAK1 and JAK2, and it received FDA approval in November 2011 for the treatment of polycythaemia vera and myelofibrosis [39,40]. Currently, ruxolitinib is approved for clinical use in 36 countries. Although the JAK2V617F mutant is the culprit in these diseases, ruxolitinib has a similar inhibitory effect on both wild-type and mutant JAK2. The adverse effects arise mainly from the lack of selectivity towards the mutant JAK2; patients who have been treated with ruxolitinib have been reported to have dose-dependent neutropenia and thrombocytopenia along with more general side effects such as fatigue, nausea and headache [41]. Importantly, adjusting the drug dosage can alleviate the leucopenia, and it is also noteworthy that ruxolitinib can be administered per orally (5–25 mg BID); therefore, patients are not required to visit the hospital for drug administration. The efficacy of ruxolitinib treatment was convincingly demonstrated in several randomized, placebo-controlled, multi-centre trials. Roughly half of the patients with myeloproliferative disorder benefitted from the treatment within the first 3 months as demonstrated by more than a 50% reduction in spleen size and systemic symptoms and improved survival. Due to the central role of JAK1 and JAK2 in the regulation of immune responses, ruxolitinib has also been studied in the treatment for autoimmune diseases [42]. Preliminary results demonstrate both efficacy and safety in a phase IIa trial in patients with rheumatoid arthritis [43]. Tofacitinib (CP690, 550, Xeljanz; Pfizer) was initially designed to be a specific inhibitor of JAK3 kinase and therefore intended primarily to be used as an immunosuppressant in transplantations and for the treatment of autoimmune diseases [44]. As mentioned above, it was expected that the specific blocking of JAK3 would result in the efficient harnessing of an overly active adaptive immunity while having minimal non-immunological side effects. More recently, it was found that tofacitinib also inhibits the kinase activity of the JAK1 enzyme but has little effect on JAK2 or TYK2 function [45,46]. However, inhibiting JAK1 is beneficial in immunosuppression; JAK1 mediates, for example, interferon and IL-6 signalling, which are the key pro-inflammatory cytokines in innate immunity [42]. Similarly to ruxolitinib, tofacitinib can also be administered per orally, and it received FDA approval for the treatment of moderately to severely active rheumatoid arthritis in November 2012 [47]. In contrast, the European Medicines Agency found the overall safety profile of Xeljanz to be inacceptable and accordingly has refused Pfizer’s application for clinical use in April 2013. Tofacitinib can be used as a monotherapy or in combination with methotrexate and/or other non-biological disease modifying antirheumatic drugs (DMARDs). There are also several ongoing clinical trials that test the usefulness of tofacitinib as an immunosuppressive agent in transplantations and in the treatment for other autoimmune diseases, such as psoriasis and colitis [42]. The adverse effects include infections, hyperlipidaemia and GI track dysfunction. Therefore, serum lipids and blood cell counts need to be monitored during the treatment.
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TARGETING THE JAK-STAT PATHWAY
The emerging new JAK inhibitors from several drug companies are also mainly intended to be used as either immunosuppressive agents or in harnessing uncontrolled cell growth in malignancies (table 1). For example, baricitinib, another JAK1/2 inhibitor both and a specific JAK3 blocker VX-509 have all demonstrated their efficacy in the treatment for arthritis [42]. There have also been at least ten phase I/II clinical trials that assess novel JAK inhibitors, such as CEP701, SB1518, CYT387, SAR302503, AZD1480 and L019 in the treatment for myeloproliferative disorders [41]. Therefore, it is plausible that we will see more JAK inhibitors in the clinic in the coming years.
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Concluding Remarks Since its discovery in the early 1990s, the JAK/STAT pathway has been under intense investigation. More than two decades of hard work was required before the approval of the first therapeutic agents that target this signalling route. In the near future, we can expect to see the launch of more compounds that target JAK kinase activity. It will be interesting to see whether the next generation of these drugs will be able to block the function of mutated JAKs, but leave the wild-type kinase unaffected. This approach has recently become more feasible; the gain-of-function mutations in myeloproliferative
Table 1. Clinical trials of JAK inhibitors. Inhibitor
JAKs affected
Ruxolitinib
JAK1, JAK2
INCB018424 Phosphate cream Tofacitinib
JAK1, JAK2
Lestaurtinib
JAK2
Baricitinib
JAK1, JAK2
SB1518 (Pacritinib)
JAK2
CYT387 SAR302503
JAK1, JAK2 JAK1, JAK2
XL019
JAK1, JAK2
VX-509 AZD1480
JAK3 JAK1, JAK2
INCB16562
JAK1, JAK2
NVP-BSK805 GLPG0634 R-348
JAK2 JAK1, JAK2, TYK2 JAK3
JAK1, JAK3
Indication
Phase
Myelofibrosis Polycythaemia vera Acute leukaemia, lymphoma Multiple myeloma Essential thrombocythaemia Prostate cancer Breast cancer Pancreatic cancer Rheumatoid arthritis Psoriasis
FDA approved FDA approved II I-II II II II II II II
Rheumatoid arthritis Ulcerative colitis Psoriasis Renal transplantation Juvenile idiopathic arthritis Dry eyes Polycythaemia vera Essential thrombocythaemia Myelofibrosis Multiple myeloma Acute leukaemia, lymphoma Neuroblastoma Psoriasis Rheumatoid arthritis Psoriasis Diabetic nephropathy Myelofibrosis Lymphoma Myelofibrosis Myelofibrosis Polycythaemia vera, essential thrombocythaemia Solid tumours Myelofibrosis Polycythaemia vera Rheumatoid arthritis Myelofibrosis Post-polycythaemia vera/essential thrombocythaemia Solid tumours Myelofibrosis Multiple myeloma Polycythaemia vera Rheumatoid arthritis Rheumatoid arthritis Dry eyes
FDA approved III III II I II I/II I/II I/II II II I II II II II I/II I/II I/II I/II II I Discontinued (high Rate of neurotoxicity) II I/II I/II I Pre-clinical Pre-clinical Pre-clinical II I I
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diseases and cancers are often in the JAK pseudokinase domain, which is now known to possess kinase activity [13]. This finding makes it a more viable target for drug design. Specific inhibition would reduce unwarranted side effects and therefore also improve the efficacy of the treatment. Also, despite several experimental attempts, we are still far from being able to provide specific and efficient STAT inhibitors for clinical use. Targeting transcription factors is not trivial, but it would enable a more specific blocking of, for example, atopic (STAT6 inhibition) or cell-mediated inflammation (STAT4 inhibition). Acknowledgements This work was financially supported by the Academy of Finland (projects 128623, 135980), a Marie Curie International Reintegration Grant within the 7th European Community Framework Programme, the Emil Aaltonen Foundation, the Sigrid Juselius Foundation, the Tampere Tuberculosis Foundation and Competitive Research Funding of the Tampere University Hospital (Grants 9M080, 9N056). Competing Financial Interests None. References 1 O’Shea JJ, Gadina M, Kanno Y. Cytokine signaling: birth of a pathway. J Immunol 2011;187:5475–8. 2 Ihle JN. Cytokine receptor signalling. Nature 1995;377:591–4. 3 Stark GR, Darnell JE Jr. The JAK-STAT pathway at twenty. Immunity 2012;36:503–14. 4 Laurence A, Pesu M, Silvennoinen O, O’Shea J. JAK kinases in health and disease: an update. Open Rheumatol J 2012;6:232–44. 5 Vahedi G, Takahashi H, Nakayamada S, Sun HW, Sartorelli V, Kanno Y, et al. STATs shape the active enhancer landscape of T cell populations. Cell 2012;151:981–93. 6 O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 2013;368:161–70. 7 O’Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 2012;36:542–50. 8 Kaplan MH, Grusby MJ. Regulation of T helper cell differentiation by STAT molecules. J Leukoc Biol 1998;64:2–5. 9 Leonard WJ, O’Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol 1998;16:293–322. 10 Yamaoka K, Saharinen P, Pesu M, Holt VE 3rd, Silvennoinen O, O’Shea JJ. The janus kinases (jaks). Genome Biol 2004;5:253. 11 Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O’Shea JJ. Therapeutic targeting of janus kinases. Immunol Rev 2008;223: 132–42. 12 Pesu M. Mutant JAK3 FERMents ATLL. Blood 2011;118:3759–60. 13 Ungureanu D, Wu J, Pekkala T, Niranjan Y, Young C, Jensen ON, et al. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat Struct Mol Biol 2011;18:971–6. 14 Bandaranayake RM, Ungureanu D, Shan Y, Shaw DE, Silvennoinen O, Hubbard SR. Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F. Nat Struct Mol Biol 2012;19:754–9. 15 Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman MJ, et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 1995;270:797–800.
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16 Yoshimura A, Misawa H. Physiology and function of the erythropoietin receptor. Curr Opin Hematol 1998;5:171–6. 17 Li Z, Gakovic M, Ragimbeau J, Eloranta ML, Ronnblom L, Michel F, et al. Two rare disease-associated Tyk2 variants are catalytically impaired but signaling competent. J Immunol 2013;190: 2335–44. 18 Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, et al. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the jaks in cytokine-induced biologic responses. Cell 1998;93:373–83. 19 Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998;93:397–409. 20 Thomis DC, Gurniak CB, Tivol E, Sharpe AH, Berg LJ. Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 1995;270:794–7. 21 Karaghiosoff M, Neubauer H, Lassnig C, Kovarik P, Schindler H, Pircher H, et al. Partial impairment of cytokine responses in Tyk2deficient mice. Immunity 2000;13:549–60. 22 Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, et al. Mutations of jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 1995;377:65–8. 23 Pesu M, Candotti F, Husa M, Hofmann SR, Notarangelo LD, O’Shea JJ. Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs. Immunol Rev 2005;203: 127–42. 24 Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 2006;25:745–55. 25 Kilic SS, Hacimustafaoglu M, Boisson-Dupuis S, Kreins AY, Grant AV, Abel L, et al. A patient with tyrosine kinase 2 deficiency without hyper-IgE syndrome. J Pediatr 2012;160:1055–7. 26 Pesu M, O’Shea J, Hennighausen L, Silvennoinen O. Identification of an acquired mutation in Jak2 provides molecular insights into the pathogenesis of myeloproliferative disorders. Mol Interv 2005;5:211–5. 27 Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054–61. 28 Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779–90. 29 James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144–8. 30 Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med 2003;349:1139–47. 31 Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 2008;452:773–6. 32 Siegel AM, Heimall J, Freeman AF, Hsu AP, Brittain E, Brenchley JM, et al. A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. Immunity 2011;35:806–18. 33 Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmaki H, Andersson EI, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med 2012;366:1905–13. 34 Rajala HL, Eldfors S, Kuusanmaki H, van Adrichem AJ, Olson T, Lagstrom S, et al. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood 2013;121:4541–50. 35 Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007;357:977–86.
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36 Korman BD, Kastner DL, Gregersen PK, Remmers EF. STAT4: genetics, mechanisms, and implications for autoimmunity. Curr Allergy Asthma Rep 2008;8:398–403. 37 Wang BX, Platanias LC, Fish EN. STAT activation in malignancies: roles in tumor progression and in the generation of antineoplastic effects of IFNs. J Interferon Cytokine Res 2013;33: 181–8. 38 O’Shea JJ, Pesu M, Borie DC, Changelian PS. A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat Rev Drug Discov 2004;3:555–64. 39 Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, CortesFranco J, Thomas DA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 2010;363:1117–27. 40 Internet. http://www.jakafi.com (last accessed on October 2013). 41 Sonbol MB, Firwana B, Zarzour A, Morad M, Rana V, Tiu RV. Comprehensive review of JAK inhibitors in myeloproliferative neoplasms. Ther Adv Hematol 2013;4:15–35.
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42 O’Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis 2013;72 (Suppl 2):ii111–5. 43 Quintas-Cardama A, Kantarjian H, Cortes J, Verstovsek S. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov 2011;10:127–40. 44 Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin WH, et al. Prevention of organ allograft rejection by a specific janus kinase 3 inhibitor. Science 2003;302:875–8. 45 Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 2008;26:127–32. 46 Meyer DM, Jesson MI, Li X, Elrick MM, Funckes-Shippy CL, Warner JD, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond) 2010;7:41. 47 Internet. http://www.xeljanz.com (last accessed on October 2013).
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