Skip to main content

Advertisement

SpringerLink
Log in

Do we know more about essential thrombocythemia because of JAK2V617F?

  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

The discovery of the JAK2V617F mutation has triggered enormous interest and some progress in our understanding of the pathogenesis of myeloproliferative disorders. This article reviews its impact upon our knowledge regarding essential thrombocythemia. The discovery of JAK2V617F has led to the proposal that essential thrombocythemia, polycythemia vera, and primary myelofibrosis be discarded as separate diagnoses, and the rationale for this change is discussed. Simplified diagnostic criteria based upon testing for JAK2V617F are proposed. Interesting data are emerging regarding disease progression and risk of complications, specifically thrombosis, pregnancy loss, and perhaps progression to myelofibrosis. The JAK2V617F allele burden is emerging as a potentially important risk factor, although its measurement is not yet standardized. It also may serve as a tool for monitoring the effects of emerging novel therapies, which hold the potential to revolutionize treatment, ranging from reducing risk of complications to potential cure. As with many important scientific discoveries, however, although the discovery of the JAK2V617F mutation has helped us to move forward, there are many new questions and many old questions still unanswered.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. James C, Ugo V, Le Couedic JP, et al.: A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005, 434:1144–1148.

    Article  PubMed  CAS  Google Scholar 

  2. Baxter EJ, Scott LM, Campbell PJ, et al.: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005, 365:1054–1061.

    PubMed  CAS  Google Scholar 

  3. 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, 7:387–397.

    Article  PubMed  CAS  Google Scholar 

  4. Kralovics R, Passamonti F, Buser AS, et al.: A gain-offunction mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005, 352:1779–1790.

    Article  PubMed  CAS  Google Scholar 

  5. Zhao R, Xing S, Li Z, et al.: Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005, 280:22788–22792.

    Article  PubMed  CAS  Google Scholar 

  6. Levine RL, Pardanani A, Tefferi A, Gilliland DG: Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 2007, 7:673–683.

    Article  PubMed  CAS  Google Scholar 

  7. Vainchenker W, Dusa A, Constantinescu SN: JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol 2008 Jul 17 (Epub ahead of print).

  8. Remacha AF, Nomdedeu JF, Puget G, et al.: Occurrence of the JAK2 V617F mutation in the WHO provisional entity: myelodysplastic/myeloproliferative disease, unclassifiable-refractory anemia with ringed sideroblasts associated with marked thrombocytosis [letter]. Haematologica 2006, 91:719–720.

    PubMed  Google Scholar 

  9. Scott LM, Tong W, Levine RL, et al.: JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007, 356:459–468.

    Article  PubMed  CAS  Google Scholar 

  10. Pietra D, Li S, Brisci A, et al.: Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood 2008, 111:1686–1689.

    Article  PubMed  CAS  Google Scholar 

  11. Pardanani AD, Levine RL, Lasho T, et al.: MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006, 108:3472–3476.

    Article  PubMed  CAS  Google Scholar 

  12. Pikman Y, Lee BH, Mercher T, et al.: MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006, 3:e270.

    Article  PubMed  Google Scholar 

  13. Vannucchi AM, Antonioli E, Guglielmelli P, et al.: Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia. Blood 2008, 112:844–847.

    Article  PubMed  CAS  Google Scholar 

  14. Williams DM, Kim AH, Rogers O, et al.: Phenotypic variations and new mutations in JAK2V617F-negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis. Exp Hematol 2007, 35:1641–1646.

    Article  PubMed  CAS  Google Scholar 

  15. Beer PA, Campbell PJ, Scott LM, et al.: MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 2008, 112:141–149.

    Article  PubMed  CAS  Google Scholar 

  16. Dameshek W: Some speculations on the myeloproliferative syndromes. Blood 1951, 6:372–375.

    PubMed  CAS  Google Scholar 

  17. Tefferi A, Thiele J, Orazi A, et al.: Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007, 110:1092–1097.

    Article  PubMed  CAS  Google Scholar 

  18. Campbell PJ, Scott LM, Buck G, et al.: Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2V617F mutation status: a prospective study. Lancet 2005, 366:1945–1953.

    Article  PubMed  CAS  Google Scholar 

  19. Wernig G, Mercher T, Okabe R, et al.: Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood 2006, 107:4274–4281.

    Article  PubMed  CAS  Google Scholar 

  20. Zaleskas VM, Krause DS, Lazarides K, et al.: Molecular pathogenesis and therapy of polycythemia induced in mice by JAK2V617F. PLoS ONE 2006, 1:e18.

    Article  PubMed  Google Scholar 

  21. Pardanani A, Fridley BL, Lasho TL, et al.: Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders. Blood 2008, 111:2785–2789.

    Article  PubMed  CAS  Google Scholar 

  22. 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, 108:2435–2437.

    Article  PubMed  CAS  Google Scholar 

  23. Plo I, Nakatake M, Malivert L, et al.: JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders. Blood 2008, 112:1402–1412.

    Article  PubMed  CAS  Google Scholar 

  24. Vannucchi AM, Antonioli E, Guglielmelli P, et al.: Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia 2008, 22:1299–1307.

    Article  PubMed  CAS  Google Scholar 

  25. Moliterno AR, Williams DM, Rogers O, Spivak JL: Molecular mimicry in the chronic myeloproliferative disorders: reciprocity between quantitative JAK2V617F and Mpl expression. Blood 2006, 108:3913–3915.

    Article  PubMed  CAS  Google Scholar 

  26. Passamonti F, Rumi E, Pietra D, et al.: Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. Blood 2006, 107:3676–3682.

    Article  PubMed  CAS  Google Scholar 

  27. Tefferi A, Lasho TL, Schwager SM, et al.: The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera. Cancer 2006, 106:631–635.

    Article  PubMed  CAS  Google Scholar 

  28. Toyama K, Karasawa M, Yamane A, et al.: JAK2-V617F mutation analysis of granulocytes and platelets from patients with chronic myeloproliferative disorders: advantage of studying platelets. Br J Haematol 2007, 139:64–69.

    Article  PubMed  CAS  Google Scholar 

  29. El-Kassar N, Hetet G, Briere J, Grandchamp B: Clonality analysis of hematopoiesis in essential thrombocythemia: advantages of studying T lymphocytes and platelets. Blood 1997, 89:128–134.

    PubMed  CAS  Google Scholar 

  30. Kralovics R, Teo SS, Li S, et al.: Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood 2006, 108:1377–1380.

    Article  PubMed  CAS  Google Scholar 

  31. Lasho TL, Pardanani A, McClure RF, 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, 135:683–687.

    Article  PubMed  CAS  Google Scholar 

  32. Nussenzveig RH, Swierczek SI, Jelinek J, et al.: Polycythemia vera is not initiated by JAK2V617F mutation. Exp Hematol 2007, 35:32–38.

    Article  PubMed  CAS  Google Scholar 

  33. Rumi E, Passamonti F, Pietra D, et al.: JAK2 (V617F) as an acquired somatic mutation and a secondary genetic event associated with disease progression in familial myeloproliferative disorders. Cancer 2006, 107:2206–2211.

    Article  PubMed  CAS  Google Scholar 

  34. Campbell PJ, Baxter EJ, Beer PA, et al.: Mutation of JAK2 in the myeloproliferative disorders: timing, clonality studies, cytogenetic associations, and role in leukemic transformation. Blood 2006, 108:3548–3555.

    Article  PubMed  CAS  Google Scholar 

  35. Theocharides A, Boissinot M, Girodon F, et al.: Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood 2007, 110:375–379.

    Article  PubMed  CAS  Google Scholar 

  36. Wilkins BS, Erber WN, Bareford D, et al.: Bone marrow pathology in essential thrombocythemia: interobserver reliability and utility for identifying disease subtypes. Blood 2008, 111:60–70.

    Article  PubMed  CAS  Google Scholar 

  37. Tefferi A: Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era. Hematology Am Soc Hematol Educ Program 2006, 240–245.

  38. Harrison CN, Green AR: Essential thrombocythaemia. Best Pract Res Clin Haematol 2006, 19:439–453.

    Article  PubMed  CAS  Google Scholar 

  39. Barbui T, Barosi G, Grossi A, et al.: Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2004, 89:215–232.

    PubMed  CAS  Google Scholar 

  40. Dahabreh IJ, Zoi K, Giannouli S, et al.: Is JAK2 V617F mutation more than a diagnostic index? A meta-analysis of clinical outcomes in essential thrombocythemia. Leuk Res 2008 Jul 14 (Epub ahead of print).

  41. Vannucchi AM, Antonioli E, Guglielmelli P, et al.: Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood 2007, 110:840–846.

    Article  PubMed  CAS  Google Scholar 

  42. Carobbio A, Finazzi G, Antonioli E, et al.: Thrombocytosis and leukocytosis interaction in vascular complications of essential thrombocythemia. Blood 2008, 112:3135–3137.

    Article  PubMed  CAS  Google Scholar 

  43. Passamonti F, Randi ML, Rumi E, et al.: Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation. Blood 2007, 110:485–489.

    Article  PubMed  CAS  Google Scholar 

  44. Mercier E, Lissalde-Lavigne G, Gris JC: JAK2V617F mutation in unexplained loss of first pregnancy [letter]. N Engl J Med 2007, 357:1984–1985.

    Article  PubMed  CAS  Google Scholar 

  45. Teofili L, Giona F, Martini M, et al.: The revised WHO diagnostic criteria for Ph-negative myeloproliferative diseases are not appropriate for the diagnostic screening of childhood polycythemia vera and essential thrombocythemia. Blood 2007, 110:3384–3386.

    Article  PubMed  CAS  Google Scholar 

  46. Verstovsek S, Kantarjian H, Pardanani A, et al.: INCB018424, an oral, selective JAK2 inhibitor, shows significant clinical activity in a phase I/II study in patients with primary myelofibrosis (PMF) and post polycythemia vera/essential thrombocythemia myelofibrosis (post-PV/ET MF) [abstract 558]. Blood (ASH Annual Meeting Abstracts) 2007, 110:558.

    Google Scholar 

  47. Kiladjian JJ, Cassinat B, Chevret S, et al.: Pegylated interferon- alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 2008, 112:3065–3072.

    Article  PubMed  CAS  Google Scholar 

  48. Ricksten A, Palmqvist L, Johansson P, Andreasson B: Rapid decline of JAK2V617F levels during hydroxyurea treatment in patients with polycythemia vera and essential thrombocythemia. Haematologica 2008, 93:1260–1261.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Haematology, Guy’s and St. Thomas’ NHS Foundation Trust, Lambeth Palace Road, London, SE1 7EH, UK

    Claire Harrison

Authors
  1. Claire Harrison
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claire Harrison.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harrison, C. Do we know more about essential thrombocythemia because of JAK2V617F?. Curr Hematol Malig Rep 4, 25–32 (2009). https://doi.org/10.1007/s11899-009-0004-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-009-0004-7

Keywords

Search

Navigation