The Gain-of-Function JAK2 V617F Mutation Shifts the Phenotype of Essential Thrombocythemia and Chronic Idiopathic Myelofibrosis to More “Erythremic” and Less “Thrombocythemic”: A Molecular, Histologic, and Clinical Study

  • Zbigniew Rudzki
  • Tomasz Sacha
  • Anastazja Stój
  • Sylwia Czekalska
  • Malgorzata Wójcik
  • Aleksander B. Skotnicki
  • Barbara Grabowska
  • Andrzej Zduńczyk
  • Krzysztof Okoń
  • Jerzy Stachura


We investigated the prevalence of the JAK2 V617F gain-of-function mutation in patients with Philadelphia chromosome-negative chronic myeloproliferative disorders (Ph- MPD) and explored the links between JAK2 mutational status and the clinicopathologic picture of essential thrombocythemia (ET), chronic idiopathic myelofibrosis (CIMF), and polycythemia vera (PV). Allele-specific polymerase chain reaction results for 59 ET, 18 CIMF, and 9 PV cases were compared with values for clinical variables at presentation and last follow-up and with the diagnostic trephine bone marrow biopsy pictures. JAK2 V617F was found in 38 (64%) of ET cases, 7 (39%) of CIMF cases, and 9 (100%) of PV cases. The ET patients with the mutant JAK2 showed significantly higher (although not overtly polycythemic) red blood cell parameter values, lower platelet counts, and higher white blood cell counts. Similar trends were found in CIMF. Megakaryocyte clustering was much less pronounced in the CIMF cases with mutant JAK2, with an analogous trend occurring in the ET cases. Bone marrow cellularity values and the numbers of CD34+ and CD117+ blasts in the ET and CIMF groups did not differ. Fibrosis was slightly less marked in the ET cases with mutant JAK2. The mutation did not significantly influence the clinical course during the follow-up in either disease in the short term (median follow-up, 22 months). The JAK2 V617F mutation is prevalent in all Ph- MPD and may skew their presenting phenotype, including bone marrow histology, toward a more “erythremic” and less “thrombocythemic” phenotype.

Key words

JAK2 Mutation Myeloproliferative disorders Trephine bone marrow biopsy 


  1. 1.
    Jaffe ES, Harris NL, Stein H, Vardiman JW, eds.World Health Organization Classification of Tumours. Pathology & Genetics: Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001:15–44.Google Scholar
  2. 2.
    Tefferi A. The Philadelphia chromosome negative chronic myelo- proliferative disorders: a practical overview.Mayo Clin Proc. 1998;73:1177–1184.PubMedCrossRefGoogle Scholar
  3. 3.
    Berlin NI. Diagnosis and classification of the polycythemias.Semin Hematol. 1975;12:339–351.PubMedGoogle Scholar
  4. 4.
    Pearson TC, Messinezy M. The diagnostic criteria of polycythaemia rubra vera.Leuk Lymphoma. 1996;22(suppl 1):87–93.PubMedGoogle Scholar
  5. 5.
    Murphy S, Peterson P, Iland H, Laszlo J. Experience of the Poly- cythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment.Semin Hematol. 1997;34:29–39.PubMedGoogle Scholar
  6. 6.
    Laszlo J. Myeloproliferative disorders (MPD): myelofibrosis, myelosclerosis, extramedullary hematopoiesis, undifferentiated MPD, and hemorrhagic thrombocythemia.Semin Hematol. 1975; 12:409–432.PubMedGoogle Scholar
  7. 7.
    Sacchi S, Vinci G, Gugliotta L, et al. Diagnosis of essential thrombocythemia at platelet counts between 400 and 600×109/L. Gruppo Italiano Malattie Mieloproliferative Croniche (GIMMC).Haema- tologica. 2000;85:492–495.Google Scholar
  8. 8.
    Michiels JJ, Thiele J. Clinical and pathological criteria for the diagnosis of essential thrombocythemia, polycythemia vera, and idio- pathic myelofibrosis (agnogenic myeloid metaplasia).Int J Hematol. 2002;76:133–145.PubMedCrossRefGoogle Scholar
  9. 9.
    Tefferi A, Deeg HJ. Deciding on transplantation for myelofibrosis: setting the record straight.Mayo Clin Proc. 2004;79:953–954.PubMedCrossRefGoogle Scholar
  10. 10.
    Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of thePDGFRA andFIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.N Engl J Med. 2003;348:1201–1214.PubMedCrossRefGoogle Scholar
  11. 11.
    Gotlib J. Molecular classification and pathogenesis of eosinophilic disorders: 2005 update.Acta Haematol. 2005;114:7–25.PubMedCrossRefGoogle Scholar
  12. 12.
    Parganas E, Wang D, Stravopodis D, et al. Jak2 is essential for signaling through a variety of cytokine receptors.Cell. 1998;93:385–395.PubMedCrossRefGoogle Scholar
  13. 13.
    Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.Lancet. 2005;365:1054–1061.PubMedGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    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.PubMedCrossRefGoogle Scholar
  16. 16.
    Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation ofJAK2 in myeloproliferative disorders.N Engl J Med. 2005;352:1779–1790.PubMedCrossRefGoogle Scholar
  17. 17.
    Saharinen P, Vihinen M, Silvennoinen O. Autoinhibition of Jak2 tyrosine kinase is dependent on specific regions in its pseudokinase domain.Mol Biol Cell. 2003;14:1448–1459.PubMedCrossRefGoogle Scholar
  18. 18.
    Tefferi A, Gilliland DG. The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis.Mayo Clin Proc. 2005;80:947–958.PubMedCrossRefGoogle Scholar
  19. 19.
    Bauermeister DE. Quantitation of bone marrow reticulin: a normal range.Am J Clin Pathol. 1971;56:24–31.PubMedGoogle Scholar
  20. 20.
    Thiele J, Kvasnicka HM, Zankovich R, Diehl V. Clinical and morphological criteria for the diagnosis of prefibrotic idiopathic (primary) myelofibrosis.Ann Hematol. 2001;80:160–165.PubMedCrossRefGoogle Scholar
  21. 21.
    Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in polycythemia vera.J Biol Chem. 2005;280:22788–22792.PubMedCrossRefGoogle Scholar
  22. 22.
    Steensma DP, Dewald GW, Lasho TL, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes.Blood. 2005;106:1207–1209.PubMedCrossRefGoogle Scholar
  23. 23.
    Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of theJAK2 V617F mutation in chronic myeloproliferative disorders.Blood. 2005;106:2162–2168.PubMedCrossRefGoogle Scholar
  24. 24.
    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;106:3370–3373.PubMedCrossRefGoogle Scholar
  25. 25.
    Scott LM, Campbell PJ, Baxter EJ, et al. The V617FJAK2 mutation is uncommon in cancers and in myeloid malignancies other than the classic myeloproliferative disorders.Blood. 2005;106:2920- 2921.PubMedCrossRefGoogle Scholar
  26. 26.
    Wolanskyj AP, Lasho TL, Schwager SM, et al.JAK2 V617F mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance.Br J Haematol. 2005;131:208–213.PubMedCrossRefGoogle Scholar
  27. 27.
    Tefferi A, Lasho TL, Schwager SM, et al. TheJAK2 V617F tyrosine kinase mutation in myelofibrosis with myeloid metaplasia: lineage specificity and clinical correlates.Br J Haematol. 2005;131:320–328.PubMedCrossRefGoogle Scholar
  28. 28.
    Tefferi A, Lasho TL, Schwager SM, et al. The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera.Cancer. 2005;106:631–635.CrossRefGoogle Scholar
  29. 29.
    Campbell PJ, Scott LM, Buck G, et al. on behalf of the United Kingdom Myeloproliferative Disorders Study Group, the Medical Research Council Adult Leukaemia Working Party and the Australasian Leukaemia and Lymphoma Group. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based onJAK2 V617F mutation status: a prospective study.Lancet. 2005;366:1945–1953.PubMedCrossRefGoogle Scholar
  30. 30.
    Campbell PJ, Griesshammer M, Döhner K, et al. The V617F mutation inJAK2 is associated with poorer survival in idiopathic myelofibrosis.Blood. 2006;107:2098–2100.PubMedCrossRefGoogle Scholar
  31. 31.
    Cheung B, Radia D, Pantelidis P, Yadegarfar G, Harrison C. The presence of theJAK2 V617F mutation is associated with a higher haemoglobin and increased risk of thrombosis in essential thrombocythaemia.Br J Haematol. 2006;132:244–245.PubMedCrossRefGoogle Scholar
  32. 32.
    Rudzki Z, Papla B, Stachura J. Chronic myeloproliferative diseases on a pathologist’s desk—a dilemma of distinct entities versus a clinico-pathologic continuum: a descriptive study based on a material from the Polish population.Pol J Pathol. 2004;55:13–23.PubMedGoogle Scholar
  33. 33.
    Jensen MK, de Nully Brown P, Nielsen OJ, Hasselbalch HC. Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area.Eur J Haematol. 2000;65:132–139.PubMedCrossRefGoogle Scholar
  34. 34.
    Harrison CN, Gale RE, Machin SJ, Linch DC. 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;93:417–424.PubMedGoogle Scholar
  35. 35.
    Lasho TL, Mesa R, Gilliland DG, Tefferi A. Mutation studies in CD3+, CD19+ and CD34+ cell fractions in myeloproliferative disorders with homozygous JAK2V617F in granulocytes.Br J Haematol. 2005;130:797–799.PubMedCrossRefGoogle Scholar
  36. 36.
    Rozman C, Giralt M, Feliu E, Rubio D, Cortes MT. Life expectancy of patients with chronic nonleukemic myeloproliferative disorders.Cancer. 1991;67:2658–2663.PubMedCrossRefGoogle Scholar
  37. 37.
    Thiele J, Kvasnicka HM. Chronic myeloproliferative disorders with thrombocythemia: a comparative study of two classification systems (PVSG, WHO) on 839 patients.Ann Hematol. 2003;82:148–152.PubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2007

Authors and Affiliations

  • Zbigniew Rudzki
    • 1
  • Tomasz Sacha
    • 2
  • Anastazja Stój
    • 1
  • Sylwia Czekalska
    • 2
  • Malgorzata Wójcik
    • 2
  • Aleksander B. Skotnicki
    • 2
  • Barbara Grabowska
    • 3
  • Andrzej Zduńczyk
    • 3
  • Krzysztof Okoń
    • 1
  • Jerzy Stachura
    • 1
  1. 1.Department of Pathomorphology, Collegium MedicumJagiellonian UniversityKrakówPoland
  2. 2.Department of Hematology, Collegium MedicumJagiellonian UniversityKrakówPoland
  3. 3.Ludwik Rydygier Memorial District HospitalKrakówPoland
  4. 4.Department of HistopathologyBirmingham Heartlands HospitalBordesleyUnited Kingdom

Personalised recommendations