JAK kinases in health and disease: An update

Open Rheumatology Journal

Volumn 6, Issue SPEC. ISSUE 2, 2012, Pages 232-244

  Laurence, Arian ^a   Pesu, Marko ^b,c   Silvennoinen, Olli ^b,c   O'Shea, John ^a  

^a NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES   (United States)

^b TAMPERE UNIVERSITY OF TECHNOLOGY   (Finland)

^c TAMPERE UNIVERSITY HOSPITAL   (Finland)

Author keywords

Autoimunity; Cancer; Cytokine signaling; Jak; Kinase inhibitors; Myelofibrosis; Tyrosine kinase

Indexed keywords

5 CHLORO N2 [1 (5 FLUORO 2 PYRIMIDINYL)ETHYL] N4 (5 METHYL 1H PYRAZOL 3 YL) 2,4 PYRIMIDINEDIAMINE; ALPHA INTERFERON; BARICITINIB; BETA INTERFERON; GAMMA INTERFERON; GLPG 0634; IMATINIB; JANUS KINASE; JANUS KINASE 1; JANUS KINASE 2; JANUS KINASE 3; JANUS KINASE INHIBITOR; LESTAURTINIB; METHOTREXATE; MOMELOTINIB; N BENZYL 2 CYANO 3 (3,4 DIHYDROXYPHENYL)ACRYLAMIDE; N TERT BUTYL 3 [5 METHYL 2 [4 [2 (1 PYRROLIDINYL)ETHOXY]PHENYLAMINO] 4 PYRIMIDINYLAMINO]BENZENESULFONAMIDE; PACRITINIB; PLACEBO; PROTEIN KINASE TYK2; PS 608504; R 348; RUXOLITINIB; STAT1 PROTEIN; STAT3 PROTEIN; STAT4 PROTEIN; TOFACITINIB; TUMOR NECROSIS FACTOR INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; VX 509;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LYMPHOBLASTIC LEUKEMIA; ASTHMA; AUTOIMMUNITY; BACTERIAL IMMUNITY; CELLULAR IMMUNITY; CHRONIC MYELOID LEUKEMIA; DOSE RESPONSE; DRUG PROTEIN BINDING; DRUG TARGETING; DRUG TOLERABILITY; ENTERITIS; ENZYME INHIBITION; ENZYME REGULATION; ENZYME STRUCTURE; ENZYME SUBSTRATE; GASTROINTESTINAL TOXICITY; GENE MUTATION; GRAFT REJECTION; HUMAN; KIDNEY GRAFT REJECTION; MYELOFIBROSIS; MYELOID METAPLASIA; MYELOPROLIFERATIVE DISORDER; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; PSORIASIS; REVIEW; RHEUMATOID ARTHRITIS; SEVERE COMBINED IMMUNODEFICIENCY; SIGNAL TRANSDUCTION; VIRUS IMMUNITY;

EID: 84870982794     PISSN: None     EISSN: 18743129     Source Type: Journal    
DOI: 10.2174/1874312901206010232     Document Type: Review

References (152)

1. Riedy MC, Dutra AS, Blake TB, et al. Genomic sequence, organization, and chromosomal localization of human JAK3. Genomics 1996; 37: 57-61.
2. Firmbach-Kraft I, Byers M, Shows T, Dalla-Favera R, Krolewski JJ. tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene 1990; 5: 1329-36.
3. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994; 264: 1415-21.
4. Decker T, Kovarik P. Serine phosphorylation of STATs. Oncogene 2000; 19: 2628-37.
5. Yang XP, Ghoreschi K, Steward-Tharp SM, et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol 2011; 12: 247-54.
6. Wei L, Vahedi G, Sun HW, et al. Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity 2010; 32: 840-51.
7. Yamaoka K, Saharinen P, Pesu M, Holt VE 3rd, Silvennoinen O, O'Shea JJ. The Janus kinases (Jaks). Genome Biol 2004; 5: 253.
8. 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.
9. Tefferi A, Sirhan S, Lasho TL, et al. Concomitant neutrophil JAK2 mutation screening and PRV-1 expression analysis in myeloproliferative disorders and secondary polycythaemia. Br J Haematol 2005; 131: 166-71.
10. Kralovics R, Teo SS, Buser AS, et al. Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2. Blood 2005; 106: 3374-6.
11. Lupardus PJ, Skiniotis G, Rice AJ, et al. Structural snapshots of full-length Jak1, a transmembrane gp130/IL-6/IL-6Ralpha cytokine receptor complex, and the receptor-Jak1 holocomplex. Structure 2011; 19: 45-55.
12. Zhou YJ, Chen M, Cusack NA, et al. Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases. Mol Cell 2001; 8: 959-69.
13. Haan S, Margue C, Engrand A, et al. Dual role of the Jak1 FERM and kinase domains in cytokine receptor binding and in stimulation-dependent Jak activation. J Immunol 2008; 180: 998-1007.
14. Boggon TJ, Li Y, Manley PW, Eck MJ. Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog. Blood 2005; 106: 996-1002.
15. Thoma G, Nuninger F, Falchetto R, et al. Identification of a potent janus kinase 3 inhibitor with high selectivity within the janus kinase family. J Med Chem 2011; 54(1): 284-8.
16. Williams NK, Bamert RS, Patel O, et al. Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J Mol Biol 2009; 387: 219-32.
17. Lucet IS, Fantino E, Styles M, et al. The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor. Blood 2006; 107: 176-83.
18. Yasukawa H, Misawa H, Sakamoto H, et al. The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J 1999; 18: 1309-20.
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. Argetsinger LS, Kouadio JL, Steen H, Stensballe A, Jensen ON, Carter-Su C. Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity. Mol Cell Biol 2004; 24: 4955-67.
21. Feener EP, Rosario F, Dunn SL, Stancheva Z, Myers MG Jr. Tyrosine phosphorylation of Jak2 in the JH2 domain inhibits cytokine signaling. Mol Cell Biol 2004; 24: 4968-78.
22. Robertson SA, Koleva RI, Argetsinger LS, et al. Regulation of Jak2 function by phosphorylation of Tyr317 and Tyr637 during cytokine signaling. Mol Cell Biol 2009; 29: 3367-78.
23. Mazurkiewicz-Munoz AM, Argetsinger LS, Kouadio JL, et al. Phosphorylation of JAK2 at serine 523: a negative regulator of JAK2 that is stimulated by growth hormone and epidermal growth factor. Mol Cell Biol 2006; 26: 4052-62.
24. Ishida-Takahashi R, Rosario F, Gong Y, et al. Phosphorylation of Jak2 on Ser(523) inhibits Jak2-dependent leptin receptor signaling. Mol Cell Biol 2006; 26: 4063-73.
25. Karaghiosoff M, Neubauer H, Lassnig C, et al. Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity 2000; 13: 549-60.
26. Shimoda K, Kato K, Aoki K, et al. Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function. Immunity 2000; 13: 561-71.
27. Saharinen P, Takaluoma K, Silvennoinen O. Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol Cell Biol 2000; 20: 3387-95.
28. Hanratty WP, Dearolf CR. The Drosophila Tumorous-lethal hematopoietic oncogene is a dominant mutation in the hopscotch locus. Mol Gen Genet 1993; 238: 33-7.
29. Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005; 280: 22788-92.
30. Minegishi Y, Saito M, Morio T, 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.
31. Szabo SJ, Sullivan BM, Peng SL, Glimcher LH. Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 2003; 21: 713-58.
32. Seto Y, Nakajima H, Suto A, et al. Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice. J Immunol 2003; 170: 1077-83.
33. Murphy CA, Langrish CL, Chen Y, et al. Divergent pro-and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003; 198: 1951-7.
34. Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421: 744-8.
35. Chen Y, Langrish CL, McKenzie B, et al. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 2006; 116: 1317-26.
36. McKenzie BS, Kastelein RA, Cua DJ. Understanding the IL-23-IL-17 immune pathway. Trends Immunol 2006; 27: 17-23.
37. Zheng Y, Valdez PA, Danilenko DM, et al. IL-22 is indispensable in early host defense against attaching and effacing bacterial pathogens. Nat Med 2008; 14: 282-9.
38. Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways with other diseases. Gut 2011; 60(12): 1739-53.
39. Watford WT, O'Shea JJ. Human tyk2 kinase deficiency: another primary immunodeficiency syndrome. Immunity 2006; 25: 695-7.
40. Rodig SJ, Meraz MA, White JM, 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.
41. Muller M, Briscoe J, Laxton C, et al. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and-gamma signal transduction. Nature 1993; 366: 129-35.
42. Rochman Y, Kashyap M, Robinson GW, et al. Thymic stromal lymphopoietin-mediated STAT5 phosphorylation via kinases JAK1 and JAK2 reveals a key difference from IL-7-induced signaling. Proc Natl Acad Sci USA 2010; 107: 19455-60.
43. Haan C, Rolvering C, Raulf F, et al. Jak1 Has a Dominant Role over Jak3 in Signal Transduction through gammac-Containing Cytokine Receptors. Chem Biol 2011; 18: 314-23.
44. Wartman LD, Larson DE, Xiang Z, et al. Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression. J Clin Invest 2011; 121: 1445-55.
45. Flex E, Petrangeli V, Stella L, et al. Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med 2008; 205: 751-8.
46. Harvey RC, Mullighan CG, Chen IM, et al. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood 2010; 115: 5312-21.
47. Asnafi V, Le Noir S, Lhermitte L, et al. JAK1 mutations are not frequent events in adult T-ALL: a GRAALL study. Br J Haematol 2010; 148: 178-9.
48. Hornakova T, Chiaretti S, Lemaire MM, et al. ALL-associated JAK1 mutations confer hypersensitivity to the antiproliferative effect of type I interferon. Blood 2010; 115: 3287-95.
49. Witthuhn BA, Quelle FW, Silvennoinen O, et al. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 1993; 74: 227-36.
50. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144-8.
51. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779-90.
52. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054-61.
53. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7: 387-97.
54. Nowell PC. Discovery of the Philadelphia chromosome: a personal perspective. J Clin Invest 2007; 117: 2033-5.
55. Druker BJ. Perspectives on the development of a molecularly targeted agent. Cancer Cell 2002; 1: 31-6.
56. Hookham MB, Elliott J, Suessmuth Y, et al. The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3. Blood 2007; 109: 4924-9.
57. Lacronique V, Boureux A, Valle VD, et al. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 1997; 278: 1309-12.
58. Carron C, Cormier F, Janin A, et al. TEL-JAK2 transgenic mice develop T-cell leukemia. Blood 2000; 95: 3891-9.
59. Kennedy JA, Barabe F, Patterson BJ, et al. Expression of TELJAK2 in primary human hematopoietic cells drives erythropoietinindependent erythropoiesis and induces myelofibrosis in vivo. Proc Natl Acad Sci USA 2006; 103: 16930-5.
60. Reiter A, Walz C, Watmore A, et al. The t(8; 9)(p22; p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. Cancer Res 2005; 65: 2662-7.
61. Bousquet M, Quelen C, De Mas V, et al. The t(8; 9)(p22; p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene. Oncogene 2005; 24: 7248-52.
62. Griesinger F, Hennig H, Hillmer F, et al. A BCR-JAK2 fusion gene as the result of a t(9; 22)(p24; q11.2) translocation in a patient with a clinically typical chronic myeloid leukemia. Genes Chrom Cancer 2005; 44: 329-33.
63. Cirmena G, Aliano S, Fugazza G, et al. A BCR-JAK2 fusion gene as the result of a t(9; 22)(p24; q11) in a patient with acute myeloid leukemia. Cancer Genet Cytogenet 2008; 183: 105-8.
64. Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5; 12) chromosomal translocation. Cell 1994; 77: 307-16.
65. Janssen JW, Ridge SA, Papadopoulos P, et al. The fusion of TEL and ABL in human acute lymphoblastic leukaemia is a rare event. Br J Haematol 1995; 90: 222-4.
66. Gaikwad A, Rye CL, Devidas M, et al. Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia. Br J Haematol 2009; 144: 930-2.
67. Kearney L, de Gonzalez CD, Yeung J, et al. Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. Blood 2009; 113: 646-8.
68. Bercovich D, Ganmore I, Scott LM, et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet 2008; 372: 1484-92.
69. Mullighan CG, Zhang J, Harvey RC, et al. JAK mutations in highrisk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA 2009; 106: 9414-8.
70. Mullighan CG, Collins-Underwood JR, Phillips LA, et al. Rearrangement of CRLF2 in B-progenitor-and Down syndromeassociated acute lymphoblastic leukemia. Nat Genet 2009; 41: 1243-6.
71. Hertzberg L, Vendramini E, Ganmore I, et al. Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group. Blood 2010; 115: 1006-17.
72. Spiekermann K, Pau M, Schwab R, Schmieja K, Franzrahe S, Hiddemann W. Constitutive activation of STAT3 and STAT5 is induced by leukemic fusion proteins with protein tyrosine kinase activity and is sufficient for transformation of hematopoietic precursor cells. Exp Hematol 2002; 30: 262-71.
73. Rottapel R, Ilangumaran S, Neale C, et al. The tumor suppressor activity of SOCS-1. Oncogene 2002; 21: 4351-62.
74. Kamizono S, Hanada T, Yasukawa H, et al. The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2. J Biol Chem 2001; 276: 12530-8.
75. Frantsve J, Schwaller J, Sternberg DW, Kutok J, Gilliland DG. Socs-1 inhibits TEL-JAK2-mediated transformation of hematopoietic cells through inhibition of JAK2 kinase activity and induction of proteasome-mediated degradation. Mol Cell Biol 2001; 21: 3547-57.
76. Dawson MA, Bannister AJ, Gottgens B, et al. JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature 2009; 461: 819-22.
77. Rui L, Emre NC, Kruhlak MJ, et al. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell 2010; 18: 590-605.
78. Rochman Y, Spolski R, Leonard WJ. New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol 2009; 9: 480-90.
79. Noguchi M, Yi H, Rosenblatt HM, et al. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 1993; 73: 147-57.
80. Russell SM, Tayebi N, Nakajima H, et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 1995; 270: 797-800.
81. Yao Z, Cui Y, Watford WT, et al. Stat5a/b are essential for normal lymphoid development and differentiation. Proc Natl Acad Sci USA 2006; 103: 1000-5.
82. Nutt SL, Urbanek P, Rolink A, Busslinger M. Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus. Genes Dev 1997; 11: 476-91.
83. Puel A, Ziegler SF, Buckley RH, Leonard WJ. Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet 1998; 20: 394-7.
84. Schorle H, Holtschke T, Hunig T, Schimpl A, Horak I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 1991; 352: 621-4.
85. Kundig TM, Schorle H, Bachmann MF, Hengartner H, Zinkernagel RM, Horak I. Immune responses in interleukin-2-deficient mice. Science 1993; 262: 1059-61.
86. Nelson BH. Interleukin-2 signaling and the maintenance of selftolerance. Curr Dir Autoimmun 2002; 5: 92-112.
87. Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 2006; 25: 195-201.
88. Sharfe N, Dadi HK, Shahar M, Roifman CM. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci USA 1997; 94: 3168-71.
89. Roifman CM. Human IL-2 receptor alpha chain deficiency. Pediatr Res 2000; 48: 6-11.
90. Lohr J, Knoechel B, Wang JJ, Villarino AV, Abbas AK. Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease. J Exp Med 2006; 203: 2785-91.
91. Laurence A, Tato CM, Davidson TS, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 2007; 26: 371-81.
92. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441: 235-8.
93. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006; 24: 179-89.
94. Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003; 198: 1875-86.
95. Yao Z, Kanno Y, Kerenyi M, et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 2007; 109: 4368-75.
96. Mathur AN, Chang HC, Zisoulis DG, et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 2007; 178: 4901-7.
97. Yang XO, Panopoulos AD, Nurieva R, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 2007; 282: 9358-63.
98. Chen Z, Laurence A, Kanno Y, et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci USA 2006; 103: 8137-42.
99. Sharfe N, Shahar M, Roifman CM. An interleukin-2 receptor gamma chain mutation with normal thymus morphology. J Clin Invest 1997; 100: 3036-43.
100. Frucht DM, Gadina M, Jagadeesh GJ, et al. Unexpected and variable phenotypes in a family with JAK3 deficiency. Genes Immun 2001; 2: 422-32.
101. Mella P, Imberti L, Brugnoni D, et al. Development of autologous T lymphocytes in two males with X-linked severe combined immune deficiency: molecular and cellular characterization. Clin Immunol 2000; 95: 39-50.
102. Brugnoni D, Notarangelo LD, Sottini A, et al. Development of autologous, oligoclonal, poorly functioning T lymphocytes in a patient with autosomal recessive severe combined immunodeficiency caused by defects of the Jak3 tyrosine kinase. Blood 1998; 91: 949-55.
103. Spolski R, Leonard WJ. IL-21 and T follicular helper cells. Int Immunol 2010; 22: 7-12.
104. Hacein-Bey-Abina S, Le Deist F, Carlier F, et al. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med 2002; 346: 1185-93.
105. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003; 302: 415-9.
106. Woods NB, Bottero V, Schmidt M, von Kalle C, Verma IM. Gene therapy: therapeutic gene causing lymphoma. Nature 2006; 440: 1123.
107. Almarza E, Zhang F, Santilli G, et al. Correction of SCID-X1 using an enhancerless Vav promoter. Hum Gene Ther 2011; 22: 263-70.
108. Birkenkamp KU, Geugien M, Lemmink HH, Kruijer W, Vellenga E. Regulation of constitutive STAT5 phosphorylation in acute myeloid leukemia blasts. Leukemia 2001; 15: 1923-31.
109. Tyner JW, Walters DK, Willis SG, et al. RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia. Blood 2008; 111: 2238-45.
110. Malinge S, Ragu C, Della-Valle V, et al. Activating mutations in human acute megakaryoblastic leukemia. Blood 2008; 112: 4220-6.
111. Walters DK, Mercher T, Gu TL, O'Hare T, Tyner JW, Loriaux M, et al. Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 2006; 10: 65-75.
112. Malamut G, El Machhour R, Montcuquet N, et al. IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest 2010; 120: 2131-43.
113. Dien Bard J, Gelebart P, Anand M, et al. IL-21 contributes to JAK3/STAT3 activation and promotes cell growth in ALK-positive anaplastic large cell lymphoma. Am J Pathol 2009; 175: 825-34.
114. Nosaka T, van Deursen JM, Tripp RA, et al. Defective lymphoid development in mice lacking Jak3. Science 1995; 270: 800-2.
115. Park SY, Saijo K, Takahashi T, et al. Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity 1995; 3: 771-82.
116. 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.
117. Ungureanu D, Saharinen P, Junttila I, Hilton DJ, Silvennoinen O. Regulation of Jak2 through the ubiquitin-proteasome pathway involves phosphorylation of Jak2 on Y1007 and interaction with SOCS-1. Mol Cell Biol 2002; 22: 3316-26.
118. Bersenev A, Wu C, Balcerek J, et al. Lnk constrains myeloproliferative diseases in mice. J Clin Invest 2010; 120: 2058-69.
119. Oh ST, Simonds EF, Jones C, et al. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood 2010; 116: 988-92.
120. Betz A, Darnell JE, Jr. A Hopscotch-chromatin connection. Nat Genet 2006; 38: 977-9.
121. Shi S, Calhoun HC, Xia F, Li J, Le L, Li WX. JAK signaling globally counteracts heterochromatic gene silencing. Nat Genet 2006; 38: 1071-6.
122. Girodon F, Steinkamp MP, Cleyrat C, Hermouet S, Wilson BS. Confocal imaging studies cast doubt on nuclear localization of JAK2V617F. Blood 2011; 118: 2633-4.
123. Jakel H, Weinl C, Hengst L. Phosphorylation of p27Kip1 by JAK2 directly links cytokine receptor signaling to cell cycle control. Oncogene 2011; 30(32): 3502-12.
124. Ghoreschi K, Jesson MI, Li X, et al. Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550). J Immunol 2011; 186: 4234-43.
125. Jiang JK, Ghoreschi K, Deflorian F, et al. Examining the chirality, conformation and selective kinase inhibition of 3-(3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550). J Med Chem 2008; 51: 8012-8.
126. Ghoreschi K, Laurence A, Yang XP, et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 2010; 467: 967-71.
127. McGeachy MJ, Chen Y, Tato CM, et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 2009; 10: 314-24.
128. Ghoreschi K, Laurence A, O'Shea JJ. Janus kinases in immune cell signaling. Immunol Rev 2009; 228: 273-87.
129. Kudlacz E, Perry B, Sawyer P, et al. The novel JAK-3 inhibitor CP-690550 is a potent immunosuppressive agent in various murine models. Am J Transplant 2004; 4: 51-7.
130. Changelian PS, Flanagan ME, Ball DJ, et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 2003; 302: 875-8.
131. Conklyn M, Andresen C, Changelian P, Kudlacz E. The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing. J Leukoc Biol 2004; 76: 1248-55.
132. Borie DC, Changelian PS, Larson MJ, et al. Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates. Transplantation 2005; 79: 791-801.
133. Paniagua R, Si MS, Flores MG, et al. Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts. Transplantation 2005; 80: 1283-92.
134. Milici AJ, Kudlacz EM, Audoly L, Zwillich S, Changelian P. Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis. Arthritis Res Ther 2008; 10: R14.
135. Paul WE, Zhu J. How are T(H)2-type immune responses initiated and amplified? Nat Rev Immunol 2010; 10: 225-35.
136. Kudlacz E, Conklyn M, Andresen C, Whitney-Pickett C, Changelian P. The JAK-3 inhibitor CP-690550 is a potent antiinflammatory agent in a murine model of pulmonary eosinophilia. Eur J Pharmacol 2008; 582: 154-61.
137. Coombs JH, Bloom BJ, Breedveld FC, et al. Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebocontrolled trial. Ann Rheum Dis 2010; 69: 413-6.
138. Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum 2009; 60: 1895-905.
139. Boy MG, Wang C, Wilkinson BE, et al. Double-blind, placebocontrolled, dose-escalation study to evaluate the pharmacologic effect of CP-690,550 in patients with psoriasis. J Invest Dermatol 2009; 129: 2299-302.
140. van Gurp E, Weimar W, Gaston R, et al. Phase 1 dose-escalation study of CP-690 550 in stable renal allograft recipients: preliminary findings of safety, tolerability, effects on lymphocyte subsets and pharmacokinetics. Am J Transplant 2008; 8: 1711-8.
141. Parganas E, Wang D, Stravopodis D, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell 1998; 93: 385-95.
142. Ju W, Zhang M, Jiang JK, et al. CP-690,550, a therapeutic agent, inhibits cytokine-mediated Jak3 activation and proliferation of T cells from patients with ATL and HAM/TSP. Blood 2011; 117: 1938-46.
143. Meydan N, Grunberger T, Dadi H, et al. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 1996; 379: 645-8.
144. 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: 1117-27.
145. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012; 366: 787-98.
146. Santos FP, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood 2010; 115: 1131-6.
147. Wernig G, Kharas MG, Okabe R, et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell 2008; 13: 311-20.
148. Geron I, Abrahamsson AE, Barroga CF, et al. Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors. Cancer Cell 2008; 13: 321-30.
149. Ioannidis S, Lamb ML, Wang T, et al. Discovery of 5-Chloro-N(2)-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N(4)-(5-methyl-1Hpyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a Novel Inhibitor of the Jak/Stat Pathway. J Med Chem 2011; 54(1): 262-76.
150. Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol 2010; 184: 5298-307.
151. Hedvat M, Huszar D, Herrmann A, et al. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell 2009; 16: 487-97.
152. Manshouri T, Quintas-Cardama A, Nussenzveig RH, et al. The JAK kinase inhibitor CP-690,550 suppresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation. Cancer Sci 2008; 99: 1265-73.