Molecular Diagnosis & Therapy

, Volume 16, Issue 5, pp 269–283 | Cite as

Current Outlook on Molecular Pathogenesis and Treatment of Myeloproliferative Neoplasms

  • Raoul Tibes
  • James M. Bogenberger
  • Kasey L. Benson
  • Ruben A. Mesa
Current Opinion


Discovery of the JAK2 V617F mutation in the myeloproliferative neoplasms (MPNs) essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) has stimulated great interest in the underlying molecular mechanisms and treatment of these diseases. Along with acceleration of technologies, novel mutations in genes such as MPL, LNK, and CBL have been discovered that converge on the JAK-STAT pathway. Several additional novel mutations in genes involved in epigenetic regulation of the genome, including TET2, ASXL1, DNMT3A, and IDH1/2, have emerged, in addition to several mutations in cellular splicing machinery. While understanding of the pathogenetic mechanisms of these novel mutations in MPNs has improved, it is still lagging behind the pace of mutation discovery. Concurrent with molecular discoveries, especially with regard to JAK-STAT signaling, therapeutic development has accelerated in recent years. More than ten JAK kinase inhibitors have been advanced into clinical trials. Recently the first JAK2 inhibitor was approved for use in patients with PMF. Most JAK-targeting agents share similar characteristics with regard to clinical benefit, consisting of improvements in splenomegaly, constitutional symptoms, and cytopenias, for example. It remains to be determined if JAK2 inhibitors can considerably impact disease progression and bone marrow histologic features (e.g., fibrosis) or significantly impact the JAK2 allele burden. While JAK2 inhibitors appear to be promising in PV and ET, they need to be compared with standard therapies, such as hydroxyurea or interferon-based therapies. Future clinical development will focus on optimal combination partners and agents that target alternative mechanisms, deepen the response, and achieve molecular remissions.


Polycythemia Vera Essential Thrombocythemia Ruxolitinib JAK2 V617F Spleen Volume 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Ruben Mesa has received research trial funding from InCyte, Genentech, Lilly, and NS Pharma. Raoul Tibes, James Bogenberger, and Kasey Benson have no conflicts of interest that are directly relevant to the content of this article. No sources of funding were used to prepare this manuscript.


  1. 1.
    Vardiman JW, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51.PubMedGoogle Scholar
  2. 2.
    Passamonti F, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients. Haematologica. 2008;93:1645–51.PubMedGoogle Scholar
  3. 3.
    Rozman C, et al. Life expectancy of patients with chronic nonleukemic myeloproliferative disorders. Cancer. 1991;67:2658–63.PubMedGoogle Scholar
  4. 4.
    Tefferi A, et al. A long-term retrospective study of young women with essential thrombocythemia. Mayo Clin Proc. 2001;76:22–8.PubMedGoogle Scholar
  5. 5.
    Landolfi R, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004;350:114–24.PubMedGoogle Scholar
  6. 6.
    Di Nisio M, et al. The haematocrit and platelet target in polycythemia vera. Br J Haematol. 2007;136:249–59.PubMedGoogle Scholar
  7. 7.
    Harrison CN, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353:33–45.PubMedGoogle Scholar
  8. 8.
    Kiladjian JJ, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112:3065–72.PubMedGoogle Scholar
  9. 9.
    Cervantes F, 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;113:2895–901.PubMedGoogle Scholar
  10. 10.
    Mesa RA. How I treat symptomatic splenomegaly in patients with myelofibrosis. Blood. 2009;113:5394–400.PubMedGoogle Scholar
  11. 11.
    Tibes R, Mesa RA. Blood consult: resistant and progressive essential thrombocythemia. Blood. 2011;118:240–2.PubMedGoogle Scholar
  12. 12.
    Barosi G, et al. Thalidomide in myelofibrosis with myeloid metaplasia: a pooled-analysis of individual patient data from five studies. Leuk Lymphoma. 2002;43:2301–7.PubMedGoogle Scholar
  13. 13.
    Mesa RA, et al. A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood. 2003;101:2534–41.PubMedGoogle Scholar
  14. 14.
    Cervantes F, et al. Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long-term results in 30 patients. Br J Haematol. 2005;129:771–5.PubMedGoogle Scholar
  15. 15.
    Lofvenberg E, et al. Reversal of myelofibrosis by hydroxyurea. Eur J Haematol. 1990;44:33–8.PubMedGoogle Scholar
  16. 16.
    Petti MC, et al. Melphalan treatment in patients with myelofibrosis with myeloid metaplasia. Br J Haematol. 2002;116:576–81.PubMedGoogle Scholar
  17. 17.
    Mesa RA, et al. Palliative goals, patient selection, and perioperative platelet management: outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic. Cancer. 2006;107:361–70.PubMedGoogle Scholar
  18. 18.
    Elliott MA, et al. Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia. Br J Haematol. 1998;103:505–11.PubMedGoogle Scholar
  19. 19.
    Ballen KK, et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transpl. 2010;16:358–67.Google Scholar
  20. 20.
    Gangat N, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29:392–7.PubMedGoogle Scholar
  21. 21.
    Passamonti F, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115:1703–8.PubMedGoogle Scholar
  22. 22.
    Quintas-Cardama A, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009;27:5418–24.PubMedGoogle Scholar
  23. 23.
    Harrison CN, et al. A large proportion of patients with a diagnosis of essential thrombocythemia do not have a clonal disorder and may be at lower risk of thrombotic complications. Blood. 1999;93:417–24.PubMedGoogle Scholar
  24. 24.
    Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010;24:1128–38.PubMedGoogle Scholar
  25. 25.
    Vannucchi AM, et al. Advances in understanding and management of myeloproliferative neoplasms. CA Cancer J Clin. 2009;59:171–91.PubMedGoogle Scholar
  26. 26.
    Baxter EJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054–61.PubMedGoogle Scholar
  27. 27.
    James C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144–8.PubMedGoogle Scholar
  28. 28.
    Levine RL, 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.PubMedGoogle Scholar
  29. 29.
    Zhao R, et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem. 2005;280:22788–92.PubMedGoogle Scholar
  30. 30.
    Kralovics R, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779–90.PubMedGoogle Scholar
  31. 31.
    Wolanskyj AP, et al. JAK2 mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance. Br J Haematol. 2005;131:208–13.PubMedGoogle Scholar
  32. 32.
    Trelinski J, et al. Circulating endothelial cells in essential thrombocythemia and polycythemia vera: correlation with JAK2-V617F mutational status, angiogenic factors and coagulation activation markers. Int J Hematol. 2010;91:792–8.PubMedGoogle Scholar
  33. 33.
    Ash RC, et al. In vitro studies of human pluripotential hematopoietic progenitors in polycythemia vera: direct evidence of stem cell involvement. J Clin Invest. 1982;69:1112–8.PubMedGoogle Scholar
  34. 34.
    Dai CH, et al. Polycythemia vera blood burst-forming units-erythroid are hypersensitive to interleukin-3. J Clin Invest. 1991;87:391–6.PubMedGoogle Scholar
  35. 35.
    Axelrad AA, et al. Hypersensitivity of circulating progenitor cells to megakaryocyte growth and development factor (PEG-rHu MGDF) in essential thrombocythemia. Blood. 2000;96:3310–21.PubMedGoogle Scholar
  36. 36.
    Jelinek J, 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;106:3370–3.PubMedGoogle Scholar
  37. 37.
    Steensma DP, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes. Blood. 2005;106:1207–9.PubMedGoogle Scholar
  38. 38.
    Scott LM, et al. The V617F JAK2 mutation is uncommon in cancers and in myeloid malignancies other than the classic myeloproliferative disorders. Blood. 2005;106:2920–1.PubMedGoogle Scholar
  39. 39.
    Beer PA, et al. Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood. 2010;115:2891–900.PubMedGoogle Scholar
  40. 40.
    Tefferi A, et al. The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera. Cancer. 2006;106:631–5.PubMedGoogle Scholar
  41. 41.
    Larsen TS, et al. The JAK2 V617F allele burden in essential thrombocythemia, polycythemia vera and primary myelofibrosis—impact on disease phenotype. Eur J Haematol. 2007;79:508–15.PubMedGoogle Scholar
  42. 42.
    Vannucchi AM, et al. Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia. 2008;22:1299–307.PubMedGoogle Scholar
  43. 43.
    Campbell PJ, et al. V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Blood. 2006;107:2098–100.PubMedGoogle Scholar
  44. 44.
    Guglielmelli P, et al. Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele. Blood. 2009;114:1477–83.PubMedGoogle Scholar
  45. 45.
    Kittur J, et al. Clinical correlates of JAK2V617F allele burden in essential thrombocythemia. Cancer. 2007;109:2279–84.PubMedGoogle Scholar
  46. 46.
    Palandri F, et al. JAK2 V617F mutation in essential thrombocythemia: correlation with clinical characteristics, response to therapy and long-term outcome in a cohort of 275 patients. Leuk Lymphoma. 2009;50:247–53.PubMedGoogle Scholar
  47. 47.
    Vannucchi AM, et al. Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden. Leukemia. 2007;21:1952–9.PubMedGoogle Scholar
  48. 48.
    Scott LM, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356:459–68.PubMedGoogle Scholar
  49. 49.
    Pardanani A, et al. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia. 2007;21:1960–3.PubMedGoogle Scholar
  50. 50.
    Barosi G, et al. Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia. 2008;22:437–8.PubMedGoogle Scholar
  51. 51.
    Antonioli E, et al. Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia. Haematologica. 2008;93:41–8.PubMedGoogle Scholar
  52. 52.
    Olcaydu D, et al. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet. 2009;41:450–4.PubMedGoogle Scholar
  53. 53.
    Jones AV, et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet. 2009;41:446–9.PubMedGoogle Scholar
  54. 54.
    Patnaik MM, et al. Chromosome 9p24 abnormalities: prevalence, description of novel JAK2 translocations, JAK2V617F mutation analysis and clinicopathologic correlates. Eur J Haematol. 2010;84:518–24.PubMedGoogle Scholar
  55. 55.
    Quentmeier H, et al. SOCS2: inhibitor of JAK2V617F-mediated signal transduction. Leukemia. 2008;22:2169–75.PubMedGoogle Scholar
  56. 56.
    Jager R, et al. Deletions of the transcription factor Ikaros in myeloproliferative neoplasms. Leukemia. 2010;24:1290–8.PubMedGoogle Scholar
  57. 57.
    Klampfl T, et al. Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression. Blood. 2011;118:167–76.PubMedGoogle Scholar
  58. 58.
    Passamonti F, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood. 2011;117:2813–6.PubMedGoogle Scholar
  59. 59.
    Scott LM. The JAK2 exon 12 mutations: a comprehensive review. Am J Hematol. 2011;86:668–76.PubMedGoogle Scholar
  60. 60.
    Pardanani AD, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood. 2006;108:3472–6.PubMedGoogle Scholar
  61. 61.
    Pikman Y, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3:e270.PubMedGoogle Scholar
  62. 62.
    Lasho TL, et al. Concurrent MPL515 and JAK2V617F mutations in myelofibrosis: chronology of clonal emergence and changes in mutant allele burden over time. Br J Haematol. 2006;135:683–7.PubMedGoogle Scholar
  63. 63.
    Vannucchi AM, et al. Constitutively activated and hyper-sensitive basophils in patients with polycythemia vera: role of JAK2V617F mutation and correlation with pruritus [abstract no. 3714]. Blood. 2008;112(11):3714.Google Scholar
  64. 64.
    Vannucchi AM, et al. Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia. Blood. 2008;112:844–7.PubMedGoogle Scholar
  65. 65.
    Guglielmelli P, et al. Anaemia characterises patients with myelofibrosis harbouring Mpl mutation. Br J Haematol. 2007;137:244–7.PubMedGoogle Scholar
  66. 66.
    Beer PA, et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood. 2008;112:141–9.PubMedGoogle Scholar
  67. 67.
    Oh ST, et al. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood. 2010;116:988–92.PubMedGoogle Scholar
  68. 68.
    Velazquez L, et al. Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice. J Exp Med. 2002;195:1599–611.PubMedGoogle Scholar
  69. 69.
    Baran-Marszak F, et al. Expression level and differential JAK2-V617F-binding of the adaptor protein Lnk regulates JAK2-mediated signals in myeloproliferative neoplasms. Blood. 2010;116:5961–71.PubMedGoogle Scholar
  70. 70.
    Sanada M, et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature. 2009;460:904–8.PubMedGoogle Scholar
  71. 71.
    Loh ML, et al. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood. 2009;114:1859–63.PubMedGoogle Scholar
  72. 72.
    Makishima H, et al. Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies. J Clin Oncol. 2009;27:6109–16.PubMedGoogle Scholar
  73. 73.
    Grand FH, et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood. 2009;113:6182–92.PubMedGoogle Scholar
  74. 74.
    Jankowska AM, et al. Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood. 2011;118:3932–41.PubMedGoogle Scholar
  75. 75.
    Mardis ER, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361:1058–66.PubMedGoogle Scholar
  76. 76.
    Figueroa ME, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553–67.PubMedGoogle Scholar
  77. 77.
    Lu C, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483:474–8.PubMedGoogle Scholar
  78. 78.
    Green A, Beer P. Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med. 2010;362:369–70.PubMedGoogle Scholar
  79. 79.
    Pardanani A, et al. LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations. Leukemia. 2010;24:1713–8.PubMedGoogle Scholar
  80. 80.
    Tefferi A, et al. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia. 2010;24:1302–9.PubMedGoogle Scholar
  81. 81.
    Ko M, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468:839–43.PubMedGoogle Scholar
  82. 82.
    Li Z, et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood. 2011;118:4509–18.PubMedGoogle Scholar
  83. 83.
    Delhommeau F, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–301.PubMedGoogle Scholar
  84. 84.
    Tefferi A, et al. Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML. Leukemia. 2009;23:1343–5.PubMedGoogle Scholar
  85. 85.
    Kosmider O, et al. TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia. Haematologica. 2009;94:1676–81.PubMedGoogle Scholar
  86. 86.
    Jankowska AM, et al. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood. 2009;113:6403–10.PubMedGoogle Scholar
  87. 87.
    Tefferi A, et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia. 2009;23:905–11.PubMedGoogle Scholar
  88. 88.
    Kosmider O, et al. TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs). Blood. 2009;114:3285–91.PubMedGoogle Scholar
  89. 89.
    Bejar R, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364:2496–506.PubMedGoogle Scholar
  90. 90.
    Abdel-Wahab O, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood. 2009;114:144–7.PubMedGoogle Scholar
  91. 91.
    Kohlmann A, et al. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol. 2010;28:3858–65.PubMedGoogle Scholar
  92. 92.
    Fisher CL, et al. A human homolog of Additional sex combs, ADDITIONAL SEX COMBS-LIKE 1, maps to chromosome 20q11. Gene. 2003;306:115–26.PubMedGoogle Scholar
  93. 93.
    Cho YS, et al. Additional sex comb-like 1 (ASXL1), in cooperation with SRC-1, acts as a ligand-dependent coactivator for retinoic acid receptor. J Biol Chem. 2006;281:17588–98.PubMedGoogle Scholar
  94. 94.
    Carbuccia N, et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia. 2009;23:2183–6.PubMedGoogle Scholar
  95. 95.
    Stein BL, et al. Disruption of the ASXL1 gene is frequent in primary, post-essential thrombocytosis and post-polycythemia vera myelofibrosis, but not essential thrombocytosis or polycythemia vera: analysis of molecular genetics and clinical phenotypes. Haematologica. 2011;96:1462–9.PubMedGoogle Scholar
  96. 96.
    Gelsi-Boyer V, et al. ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia. Br J Haematol. 2010;151:365–75.PubMedGoogle Scholar
  97. 97.
    Brecqueville M, et al. Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms. Genes Chromosomes Cancer. 2012;51(8):743–55.PubMedGoogle Scholar
  98. 98.
    Abdel-Wahab O, et al. Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms. Leukemia. 2011;25:1200–2.PubMedGoogle Scholar
  99. 99.
    Ley TJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424–33.PubMedGoogle Scholar
  100. 100.
    Stegelmann F, et al. DNMT3A mutations in myeloproliferative neoplasms. Leukemia. 2011;25:1217–9.PubMedGoogle Scholar
  101. 101.
    Guglielmelli P, et al. EZH2 mutational status predicts poor survival in myelofibrosis. Blood. 2011;118:5227–34.PubMedGoogle Scholar
  102. 102.
    Mullighan CG, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453:110–4.PubMedGoogle Scholar
  103. 103.
    Yoshida K, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478:64–9.PubMedGoogle Scholar
  104. 104.
    Papaemmanuil E, et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011;365:1384–95.PubMedGoogle Scholar
  105. 105.
    Zhang SJ, et al. Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. Blood. 2012;119:4480–5.PubMedGoogle Scholar
  106. 106.
    Mesa RA. Assessing new therapies and their overall impact in myelofibrosis. Hematol Am Soc Hematol Educ Program. 2010;2010:115–21.Google Scholar
  107. 107.
    Tibes R, Mesa RA. JAK2 inhibitors in the treatment of myeloproliferative neoplasms: rationale and clinical data. Clin Investig. 2011;1(12):1681–93. Accessed 2012 Sep 6.
  108. 108.
    Ma L, et al. Efficacy of LY2784544, a small molecule inhibitor selective for mutant JAK2 kinase, in JAK2 V617F-induced hematologic malignancy models [abstract no. 4087]. Blood. 2010;116(21):4087.Google Scholar
  109. 109.
    Quintas-Cardama A, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115:3109–17.PubMedGoogle Scholar
  110. 110.
    Verstovsek S, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363:1117–27.PubMedGoogle Scholar
  111. 111.
    Verstovsek S, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799–807.PubMedGoogle Scholar
  112. 112.
    Harrison C, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787–98.PubMedGoogle Scholar
  113. 113.
    Wernig G, 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.PubMedGoogle Scholar
  114. 114.
    Pardanani A, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011;29:789–96.PubMedGoogle Scholar
  115. 115.
    Verstovsek S, et al. Phase 1/2 study of SB1518, a novel JAK2/FLT3 inhibitor, in the treatment of primary myelofibrosis [abstract no. 3082]. Blood. 2010;116(21):3082.Google Scholar
  116. 116.
    Deeg H, et al. Phase II study of SB1518, an orally available novel JAK2 inhibitor, in patients with myelofibrosis [abstract no. 6515]. J Clin Oncol. 2011;29(15 Suppl.):6515.Google Scholar
  117. 117.
    Komrokji RS, et al. Results of a phase 2 study of pacritinib (SB1518), a novel oral JAK2 inhibitor, in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis [abstract no. 282]. Blood. 2011;118(21):282.Google Scholar
  118. 118.
    Mesa RA, 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;33:1199–203.PubMedGoogle Scholar
  119. 119.
    Tyner JW, et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood. 2010;115:5232–40.PubMedGoogle Scholar
  120. 120.
    Santos FP, 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.PubMedGoogle Scholar
  121. 121.
    Verstovsek S, et al. Phase I study of the JAK2 V617F inhibitor, LY2784544, in patients with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) [abstract no. 2814]. Blood. 2011;118(21):2814.Google Scholar
  122. 122.
    Hedvat M, et al. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell. 2009;16:487–97.PubMedGoogle Scholar
  123. 123.
    Shide K, et al. Efficacy of R723, a potent and selective JAK2 inhibitor, in JAK2V617F-induced murine MPD model [abstract no. 3897]. Blood. 2009;114(22):3897.Google Scholar
  124. 124.
    Purandare AV, et al. Characterization of BMS-911543, a functionally selective small molecule inhibitor of JAK2 [abstract no. 4112]. Blood. 2010;116(21):4112.Google Scholar
  125. 125.
    Verstovsek S, et al. Durable responses with the JAK1/JAK2 inhibitor, INCB018424, in patients with polycythemia vera (PV) and essential thrombocythemia (ET) refractory or intolerant to hydroxyurea (HU) [abstract no. 313]. Blood. 2010;116(21):313.Google Scholar
  126. 126.
    Verstovsek S, et al. RESPONSE: a randomized, open label, phase III study of INC424 in polycythemia vera (PV) patients resistant to or intolerant of hydroxyurea (HU) [abstract no. TPS203]. J Clin Oncol. 2011;29(Suppl.):TPS203.Google Scholar
  127. 127.
    Kiladjian JJ, et al. Interferon-alpha therapy in bcr-abl-negative myeloproliferative neoplasms. Leukemia. 2008;22:1990–8.PubMedGoogle Scholar
  128. 128.
    Kiladjian JJ, et al. The renaissance of interferon therapy for the treatment of myeloid malignancies. Blood. 2011;117:4706–15.PubMedGoogle Scholar
  129. 129.
    Vannucchi AM, et al. A phase 1/2 study of RAD001, a mTOR inhibitor, in patients with myelofibrosis: final results [abstract no. 314]. Blood. 2010;116(21):314.Google Scholar
  130. 130.
    Mascarenhas J, et al. A phase I study of LBH589, a novel histone deacetylase inhibitor in patients with primary myelofibrosis (PMF) and post-polycythemia/essential thrombocythemia myelofibrosis (post-PV/ET MF). Blood. 2009;114(22):308.Google Scholar
  131. 131.
    Rambaldi A, et al. A pilot study of the histone-deacetylase inhibitor givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol. 2010;150:446–55.PubMedGoogle Scholar
  132. 132.
    Rambaldi A, et al. A phase II study of the HDAC inhibitor givinostat in combination with hydroxyurea in patients with polycythemia vera resistant to hydroxyurea monotherapy [abstract no. 1748]. Blood. 2011;118(21):1748.Google Scholar
  133. 133.
    Mesa RA, et al. Phase 1/-2 study of pomalidomide in myelofibrosis. Am J Hematol. 2010;85:129–30.PubMedGoogle Scholar
  134. 134.
    Brubaker LH, et al. Treatment of anemia in myeloproliferative disorders: a randomized study of fluoxymesterone v transfusions only. Arch Intern Med. 1982;142:1533–7.PubMedGoogle Scholar
  135. 135.
    Cervantes F, et al. Danazol treatment of idiopathic myelofibrosis with severe anemia. Haematologica. 2000;85:595–9.PubMedGoogle Scholar
  136. 136.
    Levy V, et al. Treatment of agnogenic myeloid metaplasia with danazol: a report of four cases. Am J Hematol. 1996;53:239–41.PubMedGoogle Scholar
  137. 137.
    Tibes R, Mesa RA. Evolution of clinical trial endpoints in chronic myeloid leukemia: efficacious therapies require sensitive monitoring techniques. Leuk Res. 2012;36:664–71.PubMedGoogle Scholar
  138. 138.
    Deshpande A, et al. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia. 2012;26:708–15.PubMedGoogle Scholar
  139. 139.
    Hornakova T, et al. Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors. Haematologica. 2011;96:845–53.PubMedGoogle Scholar
  140. 140.
    Tibes R, Mesa RA. Myeloproliferative neoplasms 5 years after discovery of JAK2V617F: what is the impact of JAK2 inhibitor therapy? Leuk Lymphoma. 2011;52:1178–87.PubMedGoogle Scholar
  141. 141.
    Cherington C, et al. Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase. Leuk Res. 2012;36:1147–51.PubMedGoogle Scholar
  142. 142.
    Kundranda MN, et al. Transformation of a chronic myeloproliferative neoplasm to acute myelogenous leukemia: does anything work? Curr Hematol Malig Rep. 2012;7:78–86.PubMedGoogle Scholar
  143. 143.
    Pardanani A, et al. A phase I/II study of CYT387, an oral JAK-1/2 inhibitor, in myelofibrosis: significant response rates in anemia, splenomegaly, and constitutional symptoms [abstract no. 460]. Blood. 2010;116(21):460.Google Scholar
  144. 144.
    Pardanani A, et al. An expanded multicenter phase I/II study of CYT387, a JAK-1/2 inhibitor for the treatment of myelofibrosis [abstract no. 3849]. Blood. 2011;118(21):3849.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2012

Authors and Affiliations

  • Raoul Tibes
    • 1
  • James M. Bogenberger
    • 1
  • Kasey L. Benson
    • 1
  • Ruben A. Mesa
    • 1
  1. 1.Division of Hematology and Medical OncologyMayo ClinicScottsdaleUSA

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