Skip to main content
Log in

Consequences of the JAK2V617F allele burden for the prediction of transformation into myelofibrosis from polycythemia vera and essential thrombocythemia

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Patients diagnosed with polycythemia vera (PV) or essential thrombocythemia (ET) sometimes suffer transformation of the disease into myelofibrosis (MF), which is associated with a poorer prognosis. This study investigated the prognostic value of the allele burden of JAK2V617F, a somatic driver mutation in these diseases, by comparing the allele burden between formalin-fixed paraffin-embedded bone marrow collected at initial diagnosis and peripheral blood from follow-up visits. Although the annual changes in the JAK2V617F allele burden were comparable between MF-transformed (n = 11) and untransformed (n = 23) patients, the burden was significantly increased in MF-transformed patients exhibiting a longer disease duration than untransformed patients. Furthermore, MF transformation was only observed in patients whose JAK2V617F allele burden exceeded the mean values for each disease (PV, 71.7 %; ET, 35.5 %) at initial diagnosis or during follow-up. Finally, we showed that hydroxycarbamide treatment exerted neither a preventive effect on MF transformation nor a suppressive effect on the increased JAK2V617F allele burden. In conclusion, a high JAK2V617F allele burden at initial diagnosis or during follow-up is predictive of MF transformation in PV and ET. Therefore, routine measurement of the JAK2V617F allele burden using an accurate assay system is recommended to predict MF transformation.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Mesa RA, et al. MPN-associated myelofibrosis (MPN-MF). Leuk Res. 2011;35:12–3.

    Article  CAS  PubMed  Google Scholar 

  2. Tam CS, et al. Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. J Clin Oncol. 2009;27:5587–93.

    Article  PubMed  Google Scholar 

  3. Passamonti F, et al. A dynamic prognostic model to predict survival in post-polycythemia vera myelofibrosis. Blood. 2008;111:3383–7.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. Baxter EJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054–61.

    Article  CAS  PubMed  Google Scholar 

  6. Kralovics R, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779–90.

    Article  CAS  PubMed  Google Scholar 

  7. James C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144–8.

    Article  CAS  PubMed  Google Scholar 

  8. Alvarez-Larran A, et al. Postpolycythaemic myelofibrosis: frequency and risk factors for this complication in 116 patients. Br J Haematol. 2009;146:504–9.

    Article  CAS  PubMed  Google Scholar 

  9. Silver RT, et al. JAK2(V617F) allele burden in polycythemia vera correlates with grade of myelofibrosis, but is not substantially affected by therapy. Leuk Res. 2011;35:177–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Passamonti F, et al. A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia. 2010;24:1574–9.

    Article  CAS  PubMed  Google Scholar 

  11. Tefferi A, et al. The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera. Cancer. 2006;106:631–5.

    Article  CAS  PubMed  Google Scholar 

  12. Vannucchi AM, et al. Clinical profile of homozygous JAK2 617 V > F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110:840–6.

    Article  CAS  PubMed  Google Scholar 

  13. Alvarez-Larran A, et al. JAK2V617F monitoring in polycythemia vera and essential thrombocythemia: clinical usefulness for predicting myelofibrotic transformation and thrombotic events. Am J Hematol. 2014;89:517–23.

    Article  CAS  PubMed  Google Scholar 

  14. Hussein K, et al. JAK2(V617F) allele burden discriminates essential thrombocythemia from a subset of prefibrotic-stage primary myelofibrosis. Exp Hematol. 2009;37(1186–1193):e7.

    PubMed  Google Scholar 

  15. Morishita S, et al. Alternately binding probe competitive PCR as a simple, cost-effective, and accurate quantification method for JAK2V617F allele burden in myeloproliferative neoplasms. Leuk Res. 2011;3512:1632–6.

    Article  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. Rapado I, et al. Validity test study of JAK2 V617F and allele burden quantification in the diagnosis of myeloproliferative diseases. Ann Hematol. 2008;87:741–9.

    Article  CAS  PubMed  Google Scholar 

  18. Takahashi K, et al. JAK2 p. V617F detection and allele burden measurement in peripheral blood and bone marrow aspirates in patients with myeloproliferative neoplasms. Blood. 2013;122:3784–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Larsen TS, et al. Quantitative assessment of the JAK2 V617F allele burden: equivalent levels in peripheral blood and bone marrow. Leukemia. 2008;22:194–5.

    Article  CAS  PubMed  Google Scholar 

  20. Lange T, et al. JAK2 p. V617F allele burden in myeloproliferative neoplasms 1 month after allogeneic stem cell transplantation significantly predicts outcome and risk of relapse. Haematologica. 2013;98:722–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Passamonti F, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients. Haematologica. 2008;93:1645–51.

    Article  PubMed  Google Scholar 

  22. Alvarez-Larran A, et al. Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Leukemia. 2007;21:1218–23.

    Article  CAS  PubMed  Google Scholar 

  23. Barbui T, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol. 2011;29:3179–84.

    Article  PubMed  Google Scholar 

  24. Koren-Michowitz M, et al. JAK2V617F allele burden is associated with transformation to myelofibrosis. Leuk Lymphoma. 2012;53:2210–3.

    Article  CAS  PubMed  Google Scholar 

  25. Edahiro Y, et al. JAK2V617F mutation status and allele burden in classical Ph-negative myeloproliferative neoplasms in Japan. Int J Hematol. 2014;99:625–34.

    Article  CAS  PubMed  Google Scholar 

  26. Marchioli R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23:2224–32.

    Article  PubMed  Google Scholar 

  27. Ricksten A, et al. Rapid decline of JAK2V617F levels during hydroxyurea treatment in patients with polycythemia vera and essential thrombocythemia. Haematologica. 2008;93:1260–1.

    Article  CAS  PubMed  Google Scholar 

  28. Theocharides A, et al. The allele burden of JAK2 mutations remains stable over several years in patients with myeloproliferative disorders. Haematologica. 2008;93:1890–3.

    Article  PubMed  Google Scholar 

  29. Girodon F, 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;93:1723–7.

    Article  PubMed  Google Scholar 

  30. Besses C, et al. Modulation of JAK2 V617F allele burden dynamics by hydroxycarbamide in polycythaemia vera and essential thrombocythaemia patients. Br J Haematol. 2011;152:413–9.

    Article  CAS  PubMed  Google Scholar 

  31. Larsen TS, et al. Limited efficacy of hydroxyurea in lowering of the JAK2 V617F allele burden. Hematology. 2009;14:11–5.

    Article  CAS  PubMed  Google Scholar 

  32. Antonioli E, et al. Hydroxyurea does not appreciably reduce JAK2 V617F allele burden in patients with polycythemia vera or essential thrombocythemia. Haematologica. 2010;95:1435–8.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Zalcberg IR, et al. Hydroxyurea dose impacts hematologic parameters in polycythemia vera and essential thrombocythemia but does not appreciably affect JAK2-V617F allele burden. Haematologica. 2011;96:e18–20.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Kensuke Usuki (NTT Kanto Medical Center), Masafumi Ito (Japanese Red Cross Nagoya Daiichi Hospital), Makoto Kashimura (Matsudo Municipal Hospital), Shiro Tsuchiya (Soka Municipal Hospital) and Takao Hirano (Juntendo Nerima Hospital) for providing patient specimens and clinical information, Joe Matsuoka (Clinical Research Support Center, Graduate School of Medicine) for performing statistical analysis, and Satoshi Tsuneda (Department of Life Science and Medical Bioscience, Waseda University) for fruitful discussions. We also thank Kyoko Kubo, Kazuko Kawamura, Junko Enomoto, and Megumi Hasegawa for providing secretarial assistance and other members of the Department of Hematology for providing support in this study. We also acknowledge the Laboratory of Morphology and Image Analysis, Biomedical Research Center, Juntendo University Graduate School of Medicine, for technical assistance. This work was funded in part by JSPS (http://www.jsps.go.jp/english/e-grants/)KAKENHI grant #25860416 (SM) and Ministry of Education, Culture, Sports, Science and Technology, the Project for Development of Innovative Research on Cancer Therapeutics (NK, MA, SM, YE, YS). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

SM and NK hold a patent related to the method for the measurement of the JAK2V617F allele burden that was used in the present study.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Norio Komatsu.

Electronic supplementary material

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shirane, S., Araki, M., Morishita, S. et al. Consequences of the JAK2V617F allele burden for the prediction of transformation into myelofibrosis from polycythemia vera and essential thrombocythemia. Int J Hematol 101, 148–153 (2015). https://doi.org/10.1007/s12185-014-1721-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-014-1721-9

Keywords

Navigation