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Mutational subtypes of JAK2 and CALR correlate with different clinical features in Japanese patients with myeloproliferative neoplasms

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Abstract

The majority of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) harbor JAK2, CALR, or MPL mutations. We compared clinical manifestations of different subtypes of JAK2 and CALR mutations in Japanese patients with MPNs. Within our cohort, we diagnosed 166 patients as polycythemia vera (PV), 212 patients as essential thrombocythemia (ET), 23 patients as pre-primary myelofibrosis (PMF), 65 patients as overt PMF, and 27 patients as secondary myelofibrosis following the 2016 WHO criteria. Compared to patients with JAK2V617F-mutated PV, JAK2 exon 12-mutated PV patients were younger, showed lower white blood cell (WBC) counts, lower platelet counts, higher red blood cell counts, and higher frequency of thrombotic events. Compared to JAK2-mutated ET patients, CALR-mutated ET patients were younger, showed lower WBC counts, lower hemoglobin levels, higher platelet counts, and fewer thrombotic events. CALR type 1-like mutation was the dominant subtype in CALR-mutated overt PMF patients. Compared with JAK2V617F-mutated ET patients, JAK2V617F-mutated pre-PMF patients showed higher LDH levels, lower hemoglobin levels, higher JAK2V617F allele burden, and higher frequency of splenomegaly. In conclusion, Japanese patients with MPNs grouped by different mutation subtypes exhibit characteristics similar to those of their Western counterparts. In addition, ET and pre-PMF patients show different characteristics, even when restricted to JAK2V617F-mutated patients.

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References

  1. Imai M, Araki M, Komatsu N. Somatic mutations of calreticulin in myeloproliferative neoplasms. Int J Hematol. 2017;105(6):743–7.

    Article  PubMed  CAS  Google Scholar 

  2. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379–90.

    Article  PubMed  CAS  Google Scholar 

  3. Rumi E, Pietra D, Pascutto C, Guglielmelli P, Martínez-Trillos A, Casetti IC, et al. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood. 2014;124(25):2379–90.

    Google Scholar 

  4. Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, Milosevic JD, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2014;123(10):1544–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Morishita S, Komatsu N, Kirito K, Koda AH, Sekiguchi Y, Tsuneda 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;35(12):1632–6.

    Article  PubMed  CAS  Google Scholar 

  6. Rapado I, Albizua E, Ayala R, Hernández JA, Garcia-Alonso L, Grande S, et al. Validity test study of JAK2 V617F and allele burden quantification in the diagnosis of myeloproliferative diseases. Ann Hematol. 2008;87(9):741–9.

    Article  PubMed  CAS  Google Scholar 

  7. Takei H, Morishita S, Araki M, Edahiro Y, Sunami Y, Hironaka Y, et al. Detection of MPLW515L/K mutations and determination of allele frequencies with a single-tube PCR assay. PLoS One. 2014;9(8):1–8.

    Article  CAS  Google Scholar 

  8. Shirane S, Araki M, Morishita S, Edahiro Y, Takei H, Yoo Y, et al. JAK2, CALR, and MPL mutation spectrum in japanese patients with myeloproliferative neoplasms. Haematologica. 2015;100(2):e46–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Pietra D, Rumi E, Ferretti VV, Di Buduo CA, Milanesi C, Cavalloni C, et al. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia. 2016;30(2):431–8.

    Article  PubMed  CAS  Google Scholar 

  10. Arber DA, Orazi A, Hasserjian R, Borowitz MJ, Le Beau MM, Bloomfield CD, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.

    Article  PubMed  CAS  Google Scholar 

  11. Edahiro Y, Morishita S, Takahashi K, Hironaka Y, Yahata Y, Sunami Y. JAK2 V617F mutation status and allele burden in classical Ph-negative myeloproliferative neoplasms in Japan. Int J Hematol. 2014;99:625–34.

    Article  PubMed  CAS  Google Scholar 

  12. Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant. 2012;2013(48):452–8.

    Google Scholar 

  13. Tefferi A, Rumi E, Finazzi G, Gisslinger H, Vannucchi AM, Rodeghiero F, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27(9):1874–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Rumi E, Boveri E, Bellini M, Pietra D, Ferretti VV, Antonio ES, et al. Clinical course and outcome of essential thrombocythemia and prefibrotic myelofibrosis according to the revised WHO 2016 diagnostic criteria. Oncotarget. 2017;8(60):101735–44.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Guglielmelli P, Rotunno G, Fanelli T, Pacilli A, Brogi G, Calabresi L, et al. Validation of the differential prognostic impact of type 1/type 1-like versus type 2/type 2-like CALR mutations in myelofibrosis. Blood Cancer J. 2015;5:e360.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. Exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356(5):459–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Passamonti F, Elena C, Schnittger S, Skoda RC, Green AR, Girodon F, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood. 2011;117(10):2813–6.

    Article  PubMed  CAS  Google Scholar 

  18. Passamonti F, Mora B, Giorgino T, Guglielmelli P, Cazzola M, Maffioli M, et al. Driver mutations’ effect in secondary myelofibrosis: an international multicenter study based on 781 patients. Leukemia. 2017;31(4):970.

    Article  PubMed  CAS  Google Scholar 

  19. Cabagnols X, Defour JP, Ugo V, Ianotto JC, Mossuz P, Mondet J, et al. Differential association of calreticulin type 1 and type 2 mutations with myelofibrosis and essential thrombocythemia: relevance for disease evolution. Leukemia. 2015;29(1):249–52.

    Article  PubMed  CAS  Google Scholar 

  20. Marty C, Pecquet C, Nivarthi H, El-Khoury M, Chachoua I, Tulliez M, et al. Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis. Blood. 2016;127(10):1317–24.

    Article  PubMed  CAS  Google Scholar 

  21. Tefferi A, Wassie EA, Guglielmelli P, Gangat N, Belachew AA, Lasho TL, et al. Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: a collaborative study of 1027 patients. Am J Hematol. 2014;89(8):121–4.

    Article  CAS  Google Scholar 

  22. Hussein K, Bock O, Theophile K, von Neuhoff N, Buhr T, Schlué J, et al. JAK2 V617F allele burden discriminates essential thrombocythemia from a subset of prefibrotic-stage primary myelofibrosis. Exp Hematol. 2009;37(10):1186–93.

    Article  PubMed  CAS  Google Scholar 

  23. Vannucchi AM, Antonioli E, Guglielmelli P, Pardanani A, Tefferi A. Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia. 2008;22(7):1299–307.

    Article  PubMed  Google Scholar 

  24. Shirane S, Araki M, Morishita S, Edahiro Y, Sunami Y, Hironaka Y, et al. Consequences of the JAK2V617F allele burden for the prediction of transformation into myelofibrosis from polycythemia vera and essential thrombocythemia. Int J Hematol. 2015;101(2):148–53.

    Article  PubMed  CAS  Google Scholar 

  25. Barbui T, Thiele J, Passamonti F, Rumi E, Boveri E, Ruggeri M, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol. 2011;29(23):3179–84.

    Article  PubMed  Google Scholar 

  26. Gisslinger H, Jeryczynski G, Gisslinger B, Wölfler A, Burgstaller S, Buxhofer-Ausch V, et al. Clinical impact of bone marrow morphology for the diagnosis of essential thrombocythemia: comparison between the BCSH and the WHO criteria. Leukemia. 2016;30(5):1126–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We thank Masaaki Noguchi (Juntendo Urayasu Hospital), Michiaki Koike (Juntendo shizuoka Hospital) and Takao Hirano (Juntendo Nerima Hospital) for providing patient specimens and clinical data; Satoshi Tsuneda and Yuji Sekiguchi for their generous support and encouragement; Kyoko Kubo, Kazuko Kawamura, and Megumi Hasegawa for their superb secretarial assistance.

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Authors and Affiliations

  1. Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Kyohei Misawa, Hajime Yasuda, Tomonori Ochiai, Shuichi Shirane, Yoko Edahiro, Akihiko Gotoh & Norio Komatsu

  2. Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Marito Araki, Soji Morishita & Akimichi Ohsaka

Authors
  1. Kyohei Misawa
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  2. Hajime Yasuda
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  3. Marito Araki
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  4. Tomonori Ochiai
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  6. Shuichi Shirane
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  10. Norio Komatsu
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Correspondence to Norio Komatsu.

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Conflict of interest

This study was carried out as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), The Japan Agency for Medical Research and Development, and Ministry of Education, Culture, Sports, Science and Technology of Japan. Part of this work was supported by Japan Society for the Promotion of Science KAKENHI Grant #17H04211. The authors have no conflict of interest to declare.

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12185_2018_2421_MOESM1_ESM.docx

Table S1. Clinical characteristics of JAK2V617F-mutated and triple-negative pre-PMF patients. ET: essential thrombocythemia; pre-PMF: prefibrotic primary myelofibrosis. WBC: white blood cell; Hb: hemoglobin Hct: hematocrit; LDH: lactate dehydrogenase. For continuous variables, data are shown as median values and brackets represent range. For categorical variables, right side of / represents the total number of patients studied and left side represents the number of positive patients, and brackets represent positive percentages. *There was only one CALR-mutated pre-PMF patient, and thus was removed from analysis here (DOCX 15 kb)

12185_2018_2421_MOESM2_ESM.docx

Table S2. Clinical characteristics of JAK2V617F-mutated ET and JAK2V617F-mutated pre-PMF patients. JAK2-ET: JAK2V617F-mutated essential thrombocythemia; JAK2-pre-PMF: JAK2V617F-mutated prefibrotic primary myelofibrosis. WBC: white blood cell; Hb: hemoglobin; Hct: hematocrit; LDH: lactate dehydrogenase. For continuous variables, data are shown as median values and brackets represent range. For categorical variables, right side of / represents the total number of patients studied and left side represents the number of positive patients, and brackets represent positive percentage (DOCX 15 kb)

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Misawa, K., Yasuda, H., Araki, M. et al. Mutational subtypes of JAK2 and CALR correlate with different clinical features in Japanese patients with myeloproliferative neoplasms. Int J Hematol 107, 673–680 (2018). https://doi.org/10.1007/s12185-018-2421-7

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  • DOI: https://doi.org/10.1007/s12185-018-2421-7

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