Korean J Hematol.  2010 Jun;45(2):90-94. 10.5045/kjh.2010.45.2.90.

JAK2 V617F and the evolving paradigm of polycythemia vera

• Means RT

• KMID: 2083540
• DOI: http://doi.org/10.5045/kjh.2010.45.2.90

Abstract

Polycythemia vera (PV) was first described nearly 120 years ago. In the subsequent century, the clinical syndrome of PV, its natural history, its treatment, and many critical pathogenetic features of the disease were characterized. The discovery of the Janus-associated kinase - 2 mutation JAK2 V617F and the characterization of its role in myeloproliferative neoplasms have substantially changed the diagnostic paradigm for PV, and have potential to lead to new therapy and new pathogenetic insights.

Keyword

Polycythemia vera; JAK2; Myeloproliferative neoplasms; Diagnosis

MeSH Terms

Natural History
Phosphotransferases
Polycythemia
Polycythemia Vera
Phosphotransferases

Reference

1. Means RT. Greer JP, Foerster J, Rodgers GM, editors. Polycythemia vera. Wintrobe's Clinical Hematology. 2009. Baltimore, USA: Lippincott Williams & Wilkins;p. 2031–2044.

2. Gruppo Italiano Studio Policitemia. Polycythemia vera: the natural history of 1213 patients followed for 20 years. Ann Intern Med. 1995; 123:656–664. PMID: 7574220.

3. Vaquez H. Sur une forme speciale de cyanose s'accompanant d'hyperglobulie excessive et persistante. CR Soc Biol (Paris). 1892; 4:384.

4. Vaquez H, Quiserne P. Des polyglobulies. CR Soc Biol (Paris). 1902; 12:915.

5. Osler W. Chronic cyanosis with polycythemia and enlarged spleen: a new clinical entity. Am J Med Sci. 1903; 126:187–201.

6. Türk W. Beiträge zur Kenntnis des symptomenbildes Polyzythämie mit Milztumor und Zyanose. Wien Med Wochenschr. 1904; 17:153–160.

7. Osler W. Erythremia (polycythemia with cyanosis, Maladie de Vaquez). Lancet. 1908; 1:143–146.

8. Means RT Jr. Perspective: Osler's 1903 paper on polycythemia vera. Am J Med Sci. 2008; 335:418–419. PMID: 18552569.

9. Berlin NI, Wasserman LR. Polycythemia vera: a retrospective and reprise. J Lab Clin Med. 1997; 130:365–373. PMID: 9358074.

10. Berk PD, Goldberg JD, Donovan PB, Fruchtman SM, Berlin NI, Wasserman LR. Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol. 1986; 23:132–143. PMID: 3704665.

11. Pearson TC. Evaluation of diagnostic criteria in polycythemia vera. Semin Hematol. 2001; 38(1 Suppl 2):21–24. PMID: 11242598.

12. Cotes PM, Doré CJ, Yin JA, et al. Determination of serum immunoreactive erythropoietin in the investigation of erythrocytosis. N Engl J Med. 1986; 315:283–287. PMID: 3724821.

13. Birgegård G, Wide L. Serum erythropoietin in the diagnosis of polycythaemia and after phlebotomy treatment. Br J Haematol. 1992; 81:603–606. PMID: 1390249.

14. Casadevall N, Vainchenker W, Lacombe C, et al. Erythroid progenitors in polycythemia vera: demonstration of their hypersensitivity to erythropoietin using serum free cultures. Blood. 1982; 59:447–451. PMID: 7055650.

15. Moliterno AR, Spivak JL. Posttranslational processing of the thrombopoietin receptor is impaired in polycythemia vera. Blood. 1999; 94:2555–2561. PMID: 10515857.

16. Bock O, Serinsöz E, Neusch M, Schlué J, Kreipe H. The polycythaemia rubra vera-1 gene is constitutively expressed by bone marrow cells and does not discriminate polycythaemia vera from reactive and other chronic myeloproliferative disorders. Br J Haematol. 2003; 123:472–474. PMID: 14617008.

17. Michiels JJ, De Raeve H, Berneman Z, et al. The 2001 World Health Organization and updated European clinical and pathological criteria for the diagnosis, classification, and staging of the Philadelphia chromosome-negative chronic myeloproliferative disorders. Semin Thromb Hemost. 2006; 32(4 Pt 2):307–340. PMID: 16810609.

18. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005; 352:1779–1790. PMID: 15858187.

19. Ganly P, Hanrahan V, Baker B, Romeril K. Identification of JAK2V617F in patients with polycythemia is highly correlated with conventional criteria for diagnosis of polycythemia vera. Am J Hematol. 2007; 82:80–82. PMID: 16924638.

20. Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005; 106:2162–2168. PMID: 15920007.

21. Verstovsek S, Silver RT, Cross NC, Tefferi A. JAK2V617F mutational frequency in polycythemia vera: 100%, >90%, less? Leukemia. 2006; 20:2067. PMID: 16990780.

22. Scott LM, Beer PA, Bench AJ, Erber WN, Green AR. Prevalance of JAK2 V617F and exon 12 mutations in polycythaemia vera. Br J Haematol. 2007; 139:511–512. PMID: 17910642.

23. Bernardi M, Ruggeri M, Albiero E, Madeo D, Rodeghiero F. Isolated erythrocytosis in V617F negative patients with JAK2 exon 12 mutations: report of a new mutation. Am J Hematol. 2009; 84:258–260. PMID: 19229983.

24. Kouroupi E, Zoi K, Parquet N, et al. Mutations in exon 12 of JAK2 are mainly found in JAK2 V617F-negative polycythaemia vera patients. Br J Haematol. 2008; 142:676–679. PMID: 18503583.

25. Pardanani A, Lasho TL, Finke C, Hanson CA, Tefferi A. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2 V617F-negative polycythemia vera. Leukemia. 2007; 21:1960–1963. PMID: 17597810.

26. 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. PMID: 17984312.

27. Cheung B, Radia D, Pantelidis P, Yadegarfar G, Harrison C. The presence of the JAK2 V617F mutation is associated with a higher haemoglobin and increased risk of thrombosis in essential thrombocythaemia. Br J Haematol. 2006; 132:244–245. PMID: 16398659.

28. Wolanskyj AP, Lasho TL, Schwager SM, et al. JAK2 mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance. Br J Haematol. 2005; 131:208–213. PMID: 16197451.

29. Hussein K, Bock O, Theophile K, et al. JAK2(V617F) allele burden discriminates essential thrombocythemia from a subset of prefibrotic-stage primary myelofibrosis. Exp Hematol. 2009; 37:1186–1193. PMID: 19616600.

30. Sirhan S, Lasho TL, Hanson CA, Mesa RA, Pardanani A, Tefferi A. The presence of JAK2V617F in primary myelofibrosis or its allele burden in polycythemia vera predicts chemosensitivity to hydroxyurea. Am J Hematol. 2008; 83:363–365. PMID: 18266209.

31. Girodon F, Schaeffer C, Cleyrat C, et al. Frequent reduction or absence of detection of the JAK2-mutated clone in JAK2V617F-positive patients within the first years of hydroxyurea therapy. Haematologica. 2008; 93:1723–1727. PMID: 18728027.

32. Xing S, Wanting TH, Zhao W, et al. Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice. Blood. 2008; 111:5109–5117. PMID: 18334677.

33. Bumm TG, Elsea C, Corbin AS, et al. Characterization of murine JAK2V617F-positive myeloproliferative disease. Cancer Res. 2006; 66:11156–11165. PMID: 17145859.

34. Dupont S, Massé A, James C, et al. The JAK2 617V>F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera. Blood. 2007; 110:1013–1021. PMID: 17389763.

35. 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. PMID: 16675710.

36. Nussenzveig RH, Swierczek SI, Jelinek J, et al. Polycythemia vera is not initiated by JAK2V617F mutation. Exp Hematol. 2007; 35:32–38. PMID: 17198871.

37. 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. PMID: 18650451.

38. Pardanani A, Hood J, Lasho T, et al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia. 2007; 21:1658–1668. PMID: 17541402.

39. Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia. 2009; 23:1441–1445. PMID: 19295546.

40. Gozgit JM, Bebernitz G, Patil P, et al. Effects of the JAK2 inhibitor, AZ960, on Pim/BAD/BCL-xL survival signaling in the human JAK2 V617F cell line SET-2. J Biol Chem. 2008; 283:32334–32343. PMID: 18775810.

41. Santos FP, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood. 2010; 115:1131–1136. PMID: 20008298.

42. Hitoshi Y, Lin N, Payan DG, Markovtsov V. The current status and the future of JAK2 inhibitors for the treatment of myeloproliferative diseases. Int J Hematol. 2010; 91:189–200. PMID: 20191331.

43. 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. PMID: 17488875.

44. Johansson PL, Safai-Kutti S, Kutti J. An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia. Br J Haematol. 2005; 129:701–705. PMID: 15916693.

45. James C, Delhommeau F, Marzac C, et al. Detection of JAK2 V617F as a first intention diagnostic test for erythrocytosis. Leukemia. 2006; 20:350–353. PMID: 16341032.

46. Streiff MB, Smith B, Spivak JL. The diagnosis and management of polycythemia vera in the era since the Polycythemia Vera Study Group: a survey of American Society of Hematology members' practice patterns. Blood. 2002; 99:1144–1149. PMID: 11830459.

47. Means RT Jr. JAK2 V617F mutation testing in polycythemia vera: use and impact in an academic practice. Am J Med Sci. 2008; 336:327–329. PMID: 18854675.