JAK2 Inhibitors for Therapy of Myeloproliferative Neoplasms

  • Fabio P. S. Santos
  • Srdan VerstovsekEmail author
Part of the Contemporary Hematology book series (CH)


The classical Philadelphia chromosome-negative myeloproliferative ­neoplasms (Ph-negative MPNs) are hematopoietic stem cell disorders and include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) [1]. MF can also develop secondarily in patients with PV and ET (post-PV or -ET MF). Patients with PV and ET have close to normal life expectancy, but present with an increased risk for thrombosis [2]. They are usually treated with cytoreductive agents (e.g. hydroxyurea, anagrelide, 32P, busulphan, and pipobroman) which can effectively control elevated blood cell counts and decrease the risk of thrombotic phenomena, but may also be associated with an increased risk of transformation to acute myeloid leukemia (AML) and/or post-PV/ET MF [2–4]. Therefore, apart from hydroxyurea, there are few drugs available for treating these patients without incurring significant side effects. There are also few treatment options available for patients with MF [5]. Patients with MF suffer from different signs and symptoms, including massive splenomegaly, peripheral blood cytopenias, and constitutional symptoms such as fever, fatigue, and cachexia [5,6]. Treatment is palliative and symptom-directed.


Polycythemia vera Essential thrombocythemia Myelofibrosis JAK2 inhibitor JAK2 V617F 


  1. 1.
    Tefferi A, Gilliland G. Classification of chronic myeloid disorders: from Dameshek towards a semi-molecular system. Best Pract Res Clin Haematol. 2006;19(3):365–385.PubMedCrossRefGoogle Scholar
  2. 2.
    Finazzi G, Barbui T. Evidence and expertise in the management of polycythemia vera and essential thrombocythemia. Leukemia. 2008;22(8):1494–1502.PubMedCrossRefGoogle Scholar
  3. 3.
    Finazzi G, Caruso V, Marchioli R, et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood. 2005;105(7):2664–2670.PubMedCrossRefGoogle Scholar
  4. 4.
    Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353(1):33–45.PubMedCrossRefGoogle Scholar
  5. 5.
    Mesa RA, Barosi G, Cervantes F, Reilly JT, Tefferi A. Myelofibrosis with myeloid metaplasia: disease overview and non-transplant treatment options. Best Pract Res Clin Haematol. 2006;19(3):495–517.PubMedCrossRefGoogle Scholar
  6. 6.
    Mesa RA, Niblack J, Wadleigh M, et al. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD patients. Cancer. 2007;109(1):68–76.PubMedCrossRefGoogle Scholar
  7. 7.
    Kroger N, Holler E, Kobbe G, et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Blood. 2009;114(26): 5264–5270.PubMedCrossRefGoogle Scholar
  8. 8.
    Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054–1061.PubMedGoogle Scholar
  9. 9.
    James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144–1148.PubMedCrossRefGoogle Scholar
  10. 10.
    Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779–1790.PubMedCrossRefGoogle Scholar
  11. 11.
    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(4):387–397.PubMedCrossRefGoogle Scholar
  12. 12.
    Wilks AF. Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989;86(5):1603–1607.PubMedCrossRefGoogle Scholar
  13. 13.
    Leonard WJ, O’Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol. 1998;16:293–322.PubMedCrossRefGoogle Scholar
  14. 14.
    Yu H, Jove R. The STATs of cancer – new molecular targets come of age. Nat Rev Cancer. 2004;4(2):97–105.PubMedCrossRefGoogle Scholar
  15. 15.
    Giordanetto F, Kroemer RT. Prediction of the structure of human Janus kinase 2 (JAK2) comprising JAK homology domains 1 through 7. Protein Eng. 2002;15(9):727–737.PubMedCrossRefGoogle Scholar
  16. 16.
    Wilks AF, Harpur AG, Kurban RR, Ralph SJ, Zurcher G, Ziemiecki A. Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol Cell Biol. 1991;11(4):2057–2065.PubMedGoogle Scholar
  17. 17.
    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):47954–47963.PubMedCrossRefGoogle Scholar
  18. 18.
    Lindauer K, Loerting T, Liedl KR, Kroemer RT. Prediction of the structure of human Janus kinase 2 (JAK2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation. Protein Eng. 2001;14(1):27–37.PubMedCrossRefGoogle Scholar
  19. 19.
    Radtke S, Haan S, Jorissen A, et al. The Jak1 SH2 domain does not fulfill a classical SH2 function in Jak/STAT signaling but plays a structural role for receptor interaction and up-regulation of receptor surface expression. J Biol Chem. 2005;280(27):25760–25768.PubMedCrossRefGoogle Scholar
  20. 20.
    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(3):373–383.PubMedCrossRefGoogle Scholar
  21. 21.
    Parganas E, Wang D, Stravopodis D, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998;93(3):385–395.PubMedCrossRefGoogle Scholar
  22. 22.
    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(3):397–409.PubMedCrossRefGoogle Scholar
  23. 23.
    Nosaka T, van Deursen JM, Tripp RA, et al. Defective lymphoid development in mice lacking Jak3. Science. 1995;270(5237):800–802.PubMedCrossRefGoogle Scholar
  24. 24.
    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(5237):794–797.PubMedCrossRefGoogle Scholar
  25. 25.
    Macchi P, Villa A, Giliani S, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995;377(6544):65–68.PubMedCrossRefGoogle Scholar
  26. 26.
    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(5237):797–800.PubMedCrossRefGoogle Scholar
  27. 27.
    Karaghiosoff M, Neubauer H, Lassnig C, et al. Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity. 2000;13(4):549–560.PubMedCrossRefGoogle Scholar
  28. 28.
    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(4):561–571.PubMedCrossRefGoogle Scholar
  29. 29.
    Luo H, Rose P, Barber D, et al. Mutation in the Jak kinase JH2 domain hyperactivates Drosophila and mammalian Jak-Stat pathways. Mol Cell Biol. 1997;17(3):1562–1571.PubMedGoogle Scholar
  30. 30.
    Jelinek J, Oki Y, Gharibyan V, et al. JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia. Blood. 2005;106(10):3370–3373.PubMedCrossRefGoogle Scholar
  31. 31.
    Olcaydu D, Harutyunyan A, Jager R, et al. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet. 2009;41(4):450–454.PubMedCrossRefGoogle Scholar
  32. 32.
    Kilpivaara O, Mukherjee S, Schram AM, et al. A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms. Nat Genet. 2009;41(4):455–459.PubMedCrossRefGoogle Scholar
  33. 33.
    Jones AV, Chase A, Silver RT, et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet. 2009;41(4):446–449.PubMedCrossRefGoogle Scholar
  34. 34.
    Lacout C, Pisani DF, Tulliez M, Gachelin FM, Vainchenker W, Villeval JL. JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood. 2006;108(5):1652–1660.PubMedCrossRefGoogle Scholar
  35. 35.
    Wernig G, Mercher T, Okabe R, Levine RL, Lee BH, Gilliland DG. Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood. 2006;107(11):4274–4281.PubMedCrossRefGoogle Scholar
  36. 36.
    Scott LM, Scott MA, Campbell PJ, Green AR. Progenitors homozygous for the V617F mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. Blood. 2006;108(7):2435–2437.PubMedCrossRefGoogle Scholar
  37. 37.
    Campbell PJ, Scott LM, Buck G, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet. 2005;366(9501):1945–1953.PubMedCrossRefGoogle Scholar
  38. 38.
    Wolanskyj AP, Lasho TL, Schwager SM, et al. JAK2 mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance. Br J Haematol. 2005;131(2):208–213.PubMedCrossRefGoogle Scholar
  39. 39.
    Tiedt R, Hao-Shen H, Sobas MA, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood. 2008;111(8):3931–3940.PubMedCrossRefGoogle Scholar
  40. 40.
    Barosi G, Bergamaschi G, Marchetti M, et al. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood. 2007;110(12):4030–4036.PubMedCrossRefGoogle Scholar
  41. 41.
    Guglielmelli P, Barosi G, Specchia G, et al. Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele. Blood. 2009;114(8):1477–1483.PubMedCrossRefGoogle Scholar
  42. 42.
    Tefferi A, Lasho TL, Huang J, et al. Low JAK2V617F allele burden in primary myelofibrosis, compared to either a higher allele burden or unmutated status, is associated with inferior overall and leukemia-free survival. Leukemia. 2008;22(4):756–761.PubMedCrossRefGoogle Scholar
  43. 43.
    Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356(5):459–468.PubMedCrossRefGoogle Scholar
  44. 44.
    Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3(7):e270.PubMedCrossRefGoogle Scholar
  45. 45.
    Beer PA, Campbell PJ, Scott LM, et al. MPL mutations in myeloproliferative ­disorders: analysis of the PT-1 cohort. Blood. 2008;112(1):141–149.PubMedCrossRefGoogle Scholar
  46. 46.
    Nussenzveig RH, Swierczek SI, Jelinek J, et al. Polycythemia vera is not initiated by JAK2V617F mutation. Exp Hematol. 2007;35(1):32–38.PubMedCrossRefGoogle Scholar
  47. 47.
    Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360(22):2289–2301.PubMedCrossRefGoogle Scholar
  48. 48.
    Tam CS, Nussenzveig RM, Popat U, et al. The natural history and treatment outcome of blast phase BCR-ABL-myeloproliferative neoplasms. Blood. 2008;112(5):1628–1637.PubMedCrossRefGoogle Scholar
  49. 49.
    Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353(2):172–187.PubMedCrossRefGoogle Scholar
  50. 50.
    Vannucchi AM. How do JAK2-inhibitors work in myelofibrosis: an alternative hypothesis. Leuk Res. 2009;33(12):1581–1583.PubMedCrossRefGoogle Scholar
  51. 51.
    Vannucchi AM, Migliaccio AR, Paoletti F, Chagraoui H, Wendling F. Pathogenesis of myelofibrosis with myeloid metaplasia: lessons from mouse models of the disease. Semin Oncol. 2005;32(4):365–372.PubMedCrossRefGoogle Scholar
  52. 52.
    Levis M, Allebach J, Tse KF, et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood. 2002;99(11):3885–3891.PubMedCrossRefGoogle Scholar
  53. 53.
    Hexner EO, Serdikoff C, Jan M, et al. Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood. 2008;111(12):5663–5671.PubMedCrossRefGoogle Scholar
  54. 54.
    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(6):1131–1136.PubMedCrossRefGoogle Scholar
  55. 55.
    Dupriez B, Morel P, Demory JL, et al. Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood. 1996;88(3):1013–1018.PubMedGoogle Scholar
  56. 56.
    Tefferi A, Barosi G, Mesa RA, et al. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood. 2006;108(5):1497–1503.PubMedCrossRefGoogle Scholar
  57. 57.
    Smith BD, Levis M, Beran M, 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):3669–3676.PubMedCrossRefGoogle Scholar
  58. 58.
    Hexner E, Goldberg JD, Prchal JT, et al. A multicenter, open label phase I/II study of CEP701 (Lestaurtinib) in adults with myelofibrosis; a report on phase I: a study of the Myeloproliferative Disorders Research Consortium (MPD-RC) [abstract]. Blood. 2009;114(22):754.Google Scholar
  59. 59.
    Moliterno AR, Hexner E, Roboz GJ, et al. An open-label study of CEP-701 in patients with JAK2 V617F-positive PV and ET: update of 39 enrolled patients [abstract]. Blood. 2009;114(22):753.Google Scholar
  60. 60.
    Quintas-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: implications for the treatment of myeloproliferative neoplasms. Blood 2010;115(15):3109–3117.PubMedCrossRefGoogle Scholar
  61. 61.
    Verstovsek S, Kantarjian H, Mesa RA, et al. Long-term follow up and optimized dosing regimen of INCB018424 in patients with myelofibrosis: durable clinical, functional and symptomatic responses with improved hematological safety [abstract]. Blood. 2009;114(22):756.Google Scholar
  62. 62.
    Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895–2901.PubMedCrossRefGoogle Scholar
  63. 63.
    Mesa RA, Schwager S, Radia D, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res. 2009;33(9):1199–1203.PubMedCrossRefGoogle Scholar
  64. 64.
    Verstovsek S, Passamonti F, Rambaldi A, et al. A phase 2 study of INCB018424, an oral, selective JAK1/JAK2 inhibitor, in patients with advanced Polycythemia Vera (PV) and Essential Thrombocythemia (ET) refractory to hydroxyurea [abstract]. Blood. 2009;114(22):311.Google Scholar
  65. 65.
    Barosi G, Birgegard G, Finazzi G, et al. Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference. Blood. 2009;113(20):4829–4833.PubMedCrossRefGoogle Scholar
  66. 66.
    Goh KC, Ong WC, Hu C, et al. SB1518: a potent and orally active JAK2 inhibitor for the treatment of myeloproliferative disorders [abstract]. Blood. 2007;110(11):538.Google Scholar
  67. 67.
    Verstovsek S, Odenike O, Scott B, et al. Phase I dose-escalation trial of SB1518, a novel JAK2/FLT3 inhibitor, in acute and chronic myeloid diseases, including primary or post-essential thrombocythemia/polycythemia vera myelofibrosis [abstract]. Blood. 2009;114(22):3905.Google Scholar
  68. 68.
    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(4):311–320.PubMedCrossRefGoogle Scholar
  69. 69.
    Geron I, Abrahamsson AE, Barroga CF, et al. Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors. Cancer Cell. 2008;13(4):321–330.PubMedCrossRefGoogle Scholar
  70. 70.
    Pardanani AD, Gotlib JR, Jamieson C, et al. A phase I evaluation of TG101348, a selective JAK2 inhibitor, in myelofibrosis: clinical response is accompanied by significant reduction in JAK2V617F allele burden [abstract]. Blood. 2009;114(22):755.Google Scholar
  71. 71.
    Verstovsek S, Pardanani AD, Shah NP, et al. A phase I study of XL019, a selective JAK2 inhibitor, in patients with primary myelofibrosis and post-polycythemia vera/essential thrombocythemia myelofibrosis [abstract]. Blood. 2007;110(11):553.Google Scholar
  72. 72.
    Shah NP, Olszynski P, Sokol L, et al. A phase I study of XL019, a selective JAK2 inhibitor, in patients with primary myelofibrosis, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis [abstract]. Blood. 2008;112(11):98.Google Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of LeukemiaThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of HematologyHospital Israelita Albert EinsteinSão PauloBrazil

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