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.
Similar content being viewed by others
References
Mesa RA, et al. MPN-associated myelofibrosis (MPN-MF). Leuk Res. 2011;35:12–3.
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.
Passamonti F, et al. A dynamic prognostic model to predict survival in post-polycythemia vera myelofibrosis. Blood. 2008;111:3383–7.
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.
Baxter EJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054–61.
Kralovics R, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779–90.
James C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144–8.
Alvarez-Larran A, et al. Postpolycythaemic myelofibrosis: frequency and risk factors for this complication in 116 patients. Br J Haematol. 2009;146:504–9.
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.
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.
Tefferi A, et al. The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera. Cancer. 2006;106:631–5.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Passamonti F, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients. Haematologica. 2008;93:1645–51.
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.
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.
Koren-Michowitz M, et al. JAK2V617F allele burden is associated with transformation to myelofibrosis. Leuk Lymphoma. 2012;53:2210–3.
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.
Marchioli R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23:2224–32.
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.
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.
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.
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.
Larsen TS, et al. Limited efficacy of hydroxyurea in lowering of the JAK2 V617F allele burden. Hematology. 2009;14:11–5.
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.
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.
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
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-014-1721-9