Inhibitors of the JAK/STAT Pathway, with a Focus on Ruxolitinib and Similar Agents

Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 17)

Abstract

Substantive advances in our understanding of the pathogenesis of different types of lymphoma have arisen with the advent of methodologies to interrogate the genome, epigenome, and transcriptome of tumor cells. Amongst the most frequently perturbed intracellular signaling pathways identified in lymphoma is the JAK/STAT pathway, which has also been implicated in the pathogenesis of other blood cancers. Acquired mutations may affect this pathway by activating members of the JAK and STAT families directly, by inactivating those proteins whose normal function is to deactivate the JAKs, or by establishing autocrine signaling loops that drive JAK-mediated proliferation. The utilization of inhibitors of JAK/STAT activation may therefore benefit those individuals with lymphoma that are not served adequately by conventional therapies. Two JAK inhibitors, tofacitinib and ruxolitinib, are approved for use in humans currently, whilst others are under evaluation in clinical trials, and more efficacious drugs are being developed. The nature and therapeutic potential of these compounds in the treatment of patients with lymphoma are discussed.

Keywords

JAK/STAT pathway Lymphoma Resistance Ruxolitinib JAK inhibitors 

References

  1. 1.
    Saharinen P, Takaluoma K, Silvennoinen O. Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol Cell Biol. 2000;20(10):3387–95.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Saharinen P, Silvennoinen O. The pseudokinase domain is required for suppression of basal activity of Jak2 and Jak3 tyrosine kinases and for cytokine-inducible activation of signal transduction. J Biol Chem. 2002;277(49):47954–63.PubMedCrossRefGoogle Scholar
  3. 3.
    Brooks AJ, Dai W, O'Mara ML, Abankwa D, Chhabra Y, Pelekanos RA, et al. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science. 2014;344(6185):1249783.PubMedCrossRefGoogle Scholar
  4. 4.
    Rinaldi CR, Rinaldi P, Alagia A, Gemei M, Esposito N, Formiggini F, et al. Preferential nuclear accumulation of JAK2V617F in CD34+ but not in granulocytic, megakaryocytic, or erythroid cells of patients with Philadelphia-negative myeloproliferative neoplasia. Blood. 2010;116(26):6023–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Dawson MA, Bannister AJ, Gottgens B, Foster SD, Bartke T, Green AR, et al. JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature. 2009;461(7265):819–22.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Griffiths DS, Li J, Dawson MA, Trotter MW, Cheng YH, Smith AM, et al. LIF-independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cell disease. Nat Cell Biol. 2011;13(1):13–21.PubMedCrossRefGoogle Scholar
  7. 7.
    Dawson MA, Foster SD, Bannister AJ, Robson SC, Hannah R, Wang X, et al. Three distinct patterns of histone H3Y41 phosphorylation mark active genes. Cell Rep. 2012;2(3):470–7.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Pollack BP, Kotenko SV, He W, Izotova LS, Barnoski BL, Pestka S. The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity. J Biol Chem. 1999;274(44):31531–42.PubMedCrossRefGoogle Scholar
  9. 9.
    Liu F, Zhao X, Perna F, Wang L, Koppikar P, Abdel-Wahab O, et al. JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation. Cancer Cell. 2011;19(2):283–94.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Sahasrabuddhe AA, Chen X, Chung F, Velusamy T, Lim MS, Elenitoba-Johnson KS. Oncogenic Y641 mutations in EZH2 prevent Jak2/beta-TrCP-mediated degradation. Oncogene. 2015;34(4):445–54.PubMedCrossRefGoogle Scholar
  11. 11.
    Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 2002;16(22):2893–905.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298(5595):1039–43.PubMedCrossRefGoogle Scholar
  13. 13.
    Rosenwald A, Wright G, Leroy K, Yu X, Gaulard P, Gascoyne RD, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–62.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Savage KJ, Monti S, Kutok JL, Cattoretti G, Neuberg D, De Leval L, et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood. 2003;102(12):3871–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Roberti A, Dobay MP, Bisig B, Vallois D, Boechat C, Lanitis E, et al. Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations. Nat Comm. 2016;7:12602.CrossRefGoogle Scholar
  16. 16.
    Perez C, Gonzalez-Rincon J, Onaindia A, Almaraz C, Garcia-Diaz N, Pisonero H, et al. Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma. Haematologica. 2015;100(11):e450–3.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Crescenzo R, Abate F, Lasorsa E, Tabbo F, Gaudiano M, Chiesa N, et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell. 2015;27(4):516–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Joos S, Otano-Joos MI, Ziegler S, Bruderlein S, du Manoir S, Bentz M, et al. Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood. 1996;87(4):1571–8.PubMedGoogle Scholar
  19. 19.
    Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O'Donnell E, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268–77.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Eberle FC, Salaverria I, Steidl C, Summers TA Jr, Pittaluga S, Neriah SB, et al. Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations. Mod Pathol. 2011;24(12):1586–97.PubMedCrossRefGoogle Scholar
  21. 21.
    Joos S, Kupper M, Ohl S, von Bonin F, Mechtersheimer G, Bentz M, et al. Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. Cancer Res. 2000;60(3):549–52.PubMedGoogle Scholar
  22. 22.
    Roncero AM, Lopez-Nieva P, Cobos-Fernandez MA, Villa-Morales M, Gonzalez-Sanchez L, Lopez-Lorenzo JL, et al. Contribution of JAK2 mutations to T-cell lymphoblastic lymphoma development. Leukemia. 2016;30(1):94–103.PubMedCrossRefGoogle Scholar
  23. 23.
    Nairismagi ML, Tan J, Lim JQ, Nagarajan S, Ng CC, Rajasegaran V, et al. JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma. Leukemia. 2016;30(6):1311–9.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Bouchekioua A, Scourzic L, de Wever O, Zhang Y, Cervera P, Aline-Fardin A, et al. JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma. Leukemia. 2014;28(2):338–48.PubMedCrossRefGoogle Scholar
  25. 25.
    Koo GC, Tan SY, Tang T, Poon SL, Allen GE, Tan L, et al. Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma. Cancer Dis. 2012;2(7):591–7.CrossRefGoogle Scholar
  26. 26.
    Elliott NE, Cleveland SM, Grann V, Janik J, Waldmann TA, Dave UP. FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma. Blood. 2011;118(14):3911–21.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    McGirt LY, Jia P, Baerenwald DA, Duszynski RJ, Dahlman KB, Zic JA, et al. Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides. Blood. 2015;126(4):508–19.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    da Silva Almeida AC, Abate F, Khiabanian H, Martinez-Escala E, Guitart J, Tensen CP, et al. The mutational landscape of cutaneous T cell lymphoma and Sezary syndrome. Nat Genet. 2015;47(12):1465–70.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Cornejo MG, Kharas MG, Werneck MB, Le Bras S, Moore SA, Ball B, et al. Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models. Blood. 2009;113(12):2746–54.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Woollard WJ, Pullabhatla V, Lorenc A, Patel VM, Butler RM, Bayega A, et al. Candidate driver genes involved in genome maintenance and DNA repair in Sezary syndrome. Blood. 2016;127(26):3387–97.PubMedCrossRefGoogle Scholar
  31. 31.
    Couronne L, Scourzic L, Pilati C, Valle VD, Duffourd Y, Solary E, et al. STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model. Haematologica. 2013;98(11):1748–52.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Kucuk C, Jiang B, Hu X, Zhang W, Chan JK, Xiao W, et al. Activating mutations of STAT5B and STAT3 in lymphomas derived from gammadelta-T or NK cells. Nat Comm. 2015;6:6025.CrossRefGoogle Scholar
  33. 33.
    Jiang L, Gu ZH, Yan ZX, Zhao X, Xie YY, Zhang ZG, et al. Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma. Nat Genet. 2015;47(9):1061–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Ritz O, Guiter C, Castellano F, Dorsch K, Melzner J, Jais JP, et al. Recurrent mutations of the STAT6 DNA binding domain in primary mediastinal B-cell lymphoma. Blood. 2009;114(6):1236–42.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Morin RD, Assouline S, Alcaide M, Mohajeri A, Johnston RL, Chong L, et al. Genetic landscapes of relapsed and refractory diffuse large B-cell lymphomas. Clin Cancer Res. 2016;22(9):2290–300.PubMedCrossRefGoogle Scholar
  36. 36.
    Yildiz M, Li H, Bernard D, Amin NA, Ouilette P, Jones S, et al. Activating STAT6 mutations in follicular lymphoma. Blood. 2015;125(4):668–79.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Gunawardana J, Chan FC, Telenius A, Woolcock B, Kridel R, Tan KL, et al. Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma. Nat Genet. 2014;46(4):329–35.PubMedCrossRefGoogle Scholar
  38. 38.
    Kleppe M, Tousseyn T, Geissinger E, Kalender Atak Z, Aerts S, Rosenwald A, et al. Mutation analysis of the tyrosine phosphatase PTPN2 in Hodgkin's lymphoma and T-cell non-Hodgkin's lymphoma. Haematologica. 2011;96(11):1723–7.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Demosthenous C, Han JJ, Hu G, Stenson M, Gupta M. Loss of function mutations in PTPN6 promote STAT3 deregulation via JAK3 kinase in diffuse large B-cell lymphoma. Oncotarget. 2015;6(42):44703–13.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Weniger MA, Melzner I, Menz CK, Wegener S, Bucur AJ, Dorsch K, et al. Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. Oncogene. 2006;25(18):2679–84.PubMedCrossRefGoogle Scholar
  41. 41.
    Lennerz JK, Hoffmann K, Bubolz AM, Lessel D, Welke C, Ruther N, et al. Suppressor of cytokine signaling 1 gene mutation status as a prognostic biomarker in classical Hodgkin lymphoma. Oncotarget. 2015;6(30):29097–110.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Mottok A, Renne C, Seifert M, Oppermann E, Bechstein W, Hansmann ML, et al. Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities. Blood. 2009;114(20):4503–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Schif B, Lennerz JK, Kohler CW, Bentink S, Kreuz M, Melzner I, et al. SOCS1 mutation subtypes predict divergent outcomes in diffuse large B-cell lymphoma (DLBCL) patients. Oncotarget. 2013;4(1):35–47.PubMedCrossRefGoogle Scholar
  44. 44.
    Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, Davis RE, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A. 2008;105(36):13520–5.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Meier C, Hoeller S, Bourgau C, Hirschmann P, Schwaller J, Went P, et al. Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas. Mod Pathol. 2009;22(3):476–87.PubMedCrossRefGoogle Scholar
  46. 46.
    Rui L, Emre NC, Kruhlak MJ, Chung HJ, Steidl C, Slack G, et al. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell. 2010;18(6):590–605.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Cloos PA, Christensen J, Agger K, Maiolica A, Rappsilber J, Antal T, et al. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature. 2006;442(7100):307–11.PubMedCrossRefGoogle Scholar
  48. 48.
    Blombery P, Thompson ER, Jones K, Arnau GM, Lade S, Markham JF, et al. Whole exome sequencing reveals activating JAK1 and STAT3 mutations in breast implant-associated anaplastic large cell lymphoma anaplastic large cell lymphoma. Haematologica. 2016;101(9):e387–90.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Staerk J, Kallin A, Demoulin JB, Vainchenker W, Constantinescu SN. JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation: cross-talk with IGF1 receptor. J Biol Chem. 2005;280(51):41893–9.PubMedCrossRefGoogle Scholar
  50. 50.
    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(9464):1054–61.PubMedCrossRefGoogle Scholar
  51. 51.
    Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7(4):387–97.PubMedCrossRefGoogle Scholar
  52. 52.
    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(17):1779–90.PubMedCrossRefGoogle Scholar
  53. 53.
    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(7037):1144–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356(5):459–68.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Bercovich D, Ganmore I, Scott LM, Wainreb G, Birger Y, Elimelech A, et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down’s syndrome. Lancet. 2008;372(9648):1484–92.PubMedCrossRefGoogle Scholar
  56. 56.
    Mullighan CG, Zhang J, Harvey RC, Collins-Underwood JR, Schulman BA, Phillips LA, et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2009;106(23):9414–8.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Scott LM, Campbell PJ, Baxter EJ, Todd T, Stephens P, Edkins S, et al. The V617F JAK2 mutation is uncommon in cancers and in myeloid malignancies other than the classic myeloproliferative disorders. Blood. 2005;106(8):2920–1.PubMedCrossRefGoogle Scholar
  58. 58.
    Melzner I, Weniger MA, Menz CK, Moller P. Absence of the JAK2 V617F activating mutation in classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma. Leukemia. 2006;20(1):157–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Wu D, Dutra B, Lindeman N, Takahashi H, Takeyama K, Harris NL, et al. No evidence for the JAK2 (V617F) or JAK2 exon 12 mutations in primary mediastinal large B-cell lymphoma. Diagn Mol Pathol. 2009;18(3):144–9.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Van Roosbroeck K, Cox L, Tousseyn T, Lahortiga I, Gielen O, Cauwelier B, et al. JAK2 rearrangements, including the novel SEC31A-JAK2 fusion, are recurrent in classical Hodgkin lymphoma. Blood. 2011;117(15):4056–64.PubMedCrossRefGoogle Scholar
  61. 61.
    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(1):65–75.PubMedCrossRefGoogle Scholar
  62. 62.
    Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476(7360):298–303.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A. 2012;109(10):3879–84.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    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(20):1905–13.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Hu G, Witzig TE, Gupta M. A novel missense (M206K) STAT3 mutation in diffuse large B cell lymphoma deregulates STAT3 signaling. PLoS One. 2013;8(7):e67851.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Okosun J, Bodor C, Wang J, Araf S, Yang CY, Pan C, et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet. 2014;46(2):176–81.PubMedCrossRefGoogle Scholar
  67. 67.
    Mottok A, Renne C, Willenbrock K, Hansmann ML, Brauninger A. Somatic hypermutation of SOCS1 in lymphocyte-predominant Hodgkin lymphoma is accompanied by high JAK2 expression and activation of STAT6. Blood. 2007;110(9):3387–90.PubMedCrossRefGoogle Scholar
  68. 68.
    Melzner I, Bucur AJ, Bruderlein S, Dorsch K, Hasel C, Barth TF, et al. Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood. 2005;105(6):2535–42.PubMedCrossRefGoogle Scholar
  69. 69.
    Chim CS, Fung TK, Cheung WC, Liang R, Kwong YL. SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Blood. 2004;103(12):4630–5.PubMedCrossRefGoogle Scholar
  70. 70.
    Witzig TE, Hu G, Offer SM, Wellik LE, Han JJ, Stenson MJ, et al. Epigenetic mechanisms of protein tyrosine phosphatase 6 suppression in diffuse large B-cell lymphoma: implications for epigenetic therapy. Leukemia. 2014;28(1):147–54.PubMedCrossRefGoogle Scholar
  71. 71.
    Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia. N Engl J Med. 2012;367(9):826–33.PubMedCrossRefGoogle Scholar
  72. 72.
    Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470(7332):115–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Gupta M, Han JJ, Stenson M, Maurer M, Wellik L, Hu G, et al. Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation. Blood. 2012;119(12):2844–53.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Boi M, Gaudio E, Bonetti P, Kwee I, Bernasconi E, Tarantelli C, et al. The BET bromodomain inhibitor OTX015 affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs. Clin Cancer Res. 2015;21(7):1628–38.PubMedCrossRefGoogle Scholar
  75. 75.
    Ortega-Molina A, Boss IW, Canela A, Pan H, Jiang Y, Zhao C, et al. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. Nat Med. 2015;21(10):1199–208.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011;471(7337):189–95.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Spina V, Khiabanian H, Messina M, Monti S, Cascione L, Bruscaggin A, et al. The genetics of nodal marginal zone lymphoma. Blood. 2016;128(10):1362–73.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Hayakawa F, Sugimoto K, Harada Y, Hashimoto N, Ohi N, Kurahashi S, et al. A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases. Blood Cancer J. 2013;3:e166.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med. 2015;7(314):314ra185.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Burel SA, Han SR, Lee HS, Norris DA, Lee BS, Machemer T, et al. Preclinical evaluation of the toxicological effects of a novel constrained ethyl modified antisense compound targeting signal transducer and activator of transcription 3 in mice and cynomolgus monkeys. Nucleic Acid Ther. 2013;23(3):213–27.PubMedCrossRefGoogle Scholar
  81. 81.
    Sen M, Paul K, Freilino ML, Li H, Li C, Johnson DE, et al. Systemic administration of a cyclic signal transducer and activator of transcription 3 (STAT3) decoy oligonucleotide inhibits tumor growth without inducing toxicological effects. Mol Med. 2014;20:46–56.PubMedCrossRefGoogle Scholar
  82. 82.
    Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495–507.PubMedCrossRefGoogle Scholar
  83. 83.
    van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, Garcia Meijide JA, Wagner S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508–19.PubMedCrossRefGoogle Scholar
  84. 84.
    Pemmaraju N, Kantarjian H, Kadia T, Cortes J, Borthakur G, Newberry K, et al. A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia. Clin Lymphoma Myeloma Leukemia. 2015;15(3):171–6.CrossRefGoogle Scholar
  85. 85.
    Punwani N, Burn T, Scherle P, Flores R, Shi J, Collier P, et al. Downmodulation of key inflammatory cell markers with a topical Janus kinase 1/2 inhibitor. Br J Dermatol. 2015;173(4):989–97.PubMedCrossRefGoogle Scholar
  86. 86.
    Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014;20(9):1043–9.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Hurwitz HI, Uppal N, Wagner SA, Bendell JC, Beck JT, Wade SM 3rd, et al. Randomized, double-blind, phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. J Clin Oncol. 2015;33(34):4039–47.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Younes A, Romaguera J, Fanale M, McLaughlin P, Hagemeister F, Copeland A, et al. Phase I study of a novel oral Janus kinase 2 inhibitor, SB1518, in patients with relapsed lymphoma: evidence of clinical and biologic activity in multiple lymphoma subtypes. J Clin Oncol. 2012;30(33):4161–7.PubMedCrossRefGoogle Scholar
  89. 89.
    Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117–27.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–98.PubMedCrossRefGoogle Scholar
  92. 92.
    Ma J, Xing W, Coffey G, Dresser K, Lu K, Guo A, et al. Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma. Oncotarget. 2015;6(41):43881–96.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011;29(7):789–96.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Hao Y, Chapuy B, Monti S, Sun HH, Rodig SJ, Shipp MA. Selective JAK2 inhibition specifically decreases Hodgkin lymphoma and mediastinal large B-cell lymphoma growth in vitro and in vivo. Clin Cancer Res. 2014;20(10):2674–83.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Sandborn WJ, Ghosh S, Panes J, Vranic I, Su C, Rousell S, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012;367(7):616–24.PubMedCrossRefGoogle Scholar
  96. 96.
    Abdelrahman RA, Begna KH, Al-Kali A, Hogan WJ, Litzow MR, Pardanani A, et al. Momelotinib treatment-emergent neuropathy: prevalence, risk factors and outcome in 100 patients with myelofibrosis. Br J Haematol. 2015;169(1):77–80.PubMedCrossRefGoogle Scholar
  97. 97.
    Monaghan KA, Khong T, Burns CJ, Spencer A. The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. Leukemia. 2011;25(12):1891–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Derenzini E, Lemoine M, Buglio D, Katayama H, Ji Y, Davis RE, et al. The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma. Blood Cancer J. 2011;1(12):e46.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Levis M, Allebach J, Tse KF, Zheng R, Baldwin BR, Smith BD, et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood. 2002;99(11):3885–91.PubMedCrossRefGoogle Scholar
  100. 100.
    Smith BD, Levis M, Beran M, Giles F, Kantarjian H, Berg K, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004;103(10):3669–76.PubMedCrossRefGoogle Scholar
  101. 101.
    Hexner E, Roboz G, Hoffman R, Luger S, Mascarenhas J, Carroll M, et al. Open-label study of oral CEP-701 (lestaurtinib) in patients with polycythaemia vera or essential thrombocythaemia with JAK2-V617F mutation. Br J Haematol. 2014;164(1):83–93.PubMedCrossRefGoogle Scholar
  102. 102.
    Santos FP, Kantarjian HM, Jain N, Manshouri T, Thomas DA, Garcia-Manero G, 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(6):1131–6.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Beck D, Zobel J, Barber R, Evans S, Lezina L, Allchin RL, et al. Synthetic lethal screen demonstrates that a JAK2 inhibitor suppresses a BCL6-dependent IL10RA/JAK2/STAT3 pathway in high grade B-cell lymphoma. J Biol Chem. 2016;291(32):16686–98.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Schoof N, von Bonin F, Trumper L, Kube D. HSP90 is essential for Jak-STAT signaling in classical Hodgkin lymphoma cells. Cell Commun Signal. 2009;7:17.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Marubayashi S, Koppikar P, Taldone T, Abdel-Wahab O, West N, Bhagwat N, et al. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J Clin Invest. 2010;120(10):3578–93.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Weigert O, Lane AA, Bird L, Kopp N, Chapuy B, van Bodegom D, et al. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J Exp Med. 2012;209(2):259–73.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039–43.PubMedCrossRefGoogle Scholar
  108. 108.
    Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ, et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012;485(7397):260–3.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293(5531):876–80.PubMedCrossRefGoogle Scholar
  110. 110.
    Deshpande A, Reddy MM, Schade GO, Ray A, Chowdary TK, Griffin JD, et al. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia. 2012;26(4):708–15.PubMedCrossRefGoogle Scholar
  111. 111.
    Marit MR, Chohan M, Matthew N, Huang K, Kuntz DA, Rose DR, et al. Random mutagenesis reveals residues of JAK2 critical in evading inhibition by a tyrosine kinase inhibitor. PLoS One. 2012;7(8):e43437.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Hornakova T, Springuel L, Devreux J, Dusa A, Constantinescu SN, Knoops L, et al. Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors. Haematologica. 2011;96(6):845–53.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Koppikar P, Bhagwat N, Kilpivaara O, Manshouri T, Adli M, Hricik T, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012;489(7414):155–9.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Meyer SC, Keller MD, Chiu S, Koppikar P, Guryanova OA, Rapaport F, et al. CHZ868, a type II JAK2 inhibitor, reverses type I JAK inhibitor persistence and demonstrates efficacy in myeloproliferative neoplasms. Cancer Cell. 2015;28(1):15–28.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Andraos R, Qian Z, Bonenfant D, Rubert J, Vangrevelinghe E, Scheufler C, et al. Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent. Cancer Dis. 2012;2(6):512–23.CrossRefGoogle Scholar
  116. 116.
    Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3(7):e270.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Wu SC, Li LS, Kopp N, Montero J, Chapuy B, Yoda A, et al. Activity of the type II JAK2 inhibitor CHZ868 in B cell acute lymphoblastic leukemia. Cancer Cell. 2015;28(1):29–41.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.The University of Queensland Diamantina Institute, The University of Queensland, Translational Research InstituteBrisbaneAustralia

Personalised recommendations