Annals of Laboratory Medicine

Korean Society for Laboratory Medicine (대한진단검사의학회)
권호 표지
DOI QR코드

DOI QR Code

Correlations between Janus Kinase 2 V617F Allele Burdens and Clinicohematologic Parameters in Myeloproliferative Neoplasms

  • Ha, Jung-Sook (Department of Laboratory Medicine, Keimyung University School of Medicine) ;
  • Kim, Yu-Kyung (Department of Laboratory Medicine, Kyungbook National University School of Medicine) ;
  • Jung, Soon-Il (Department of Laboratory Medicine, Yeungnam University College of Medicine) ;
  • Jung, He-Ra (Department of Pathology, Keimyung University School of Medicine) ;
  • Chung, In-Sung (Department of Occupational and Environmental Medicine, Keimyung University School of Medicine)
  • Published : 2012.11.01
⟨ Previous Next ⟩

Abstract

Background: This study evaluated potential correlations between the allele burden of the Janus kinase 2 (JAK2) V617F mutation and clinicohematologic characteristics in patients with myeloproliferative neoplasms (MPN). Methods: Clinical and hematologic features were reviewed for 103 MPN patients, including patients with polycythemia vera (PV, 22 patients), essential thrombocythemia (ET, 64 patients), and primary myelofibrosis (PMF, 17 patients). JAK2 V617F allele status and allele burdens were measured by allele-specific PCR and pyrosequencing, respectively. Results: The JAK2 V617F mutation was detected in 95.5%, 68.8%, and 52.9% of PV, ET, and PMF patients, respectively. JAK2 V617F-positive ET patients were significantly older and exhibited higher neutrophil fractions, a higher frequency of thrombotic events, and a higher myelofibrosis rate than JAK2 V617F-negative patients (P <0.05). PV patients carried the highest mean T allele burden (66.0%${\pm}$24.9%) compared with ET (40.5%${\pm}$25.2%) and PMF patients (31.5%${\pm}$37.0%) (P =0.00). No significant correlations were detected between V617F allele burden and patient age, white blood cell count, Hb, Hct, or the platelet count for PV, ET, or PMF patients. ET patients with organomegaly had a higher JAK2 V617F allele burden (53.4%${\pm}$23.7%) than patients without organomegaly (35.6%${\pm}$24.3%) (P =0.03). Conclusions: The JAK2 V617F mutational status and its allele burden correlate with the clinicohematologic phenotypes of ET patients, including older age, higher neutrophil count, and greater rates of organomegaly, thrombotic events, and myelofibrosis. For PV and PMF patients, larger-scale studies involving more MPN patients are needed.

Keywords

References

  1. Tefferi A and Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22:14-22. https://doi.org/10.1038/sj.leu.2404955
  2. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779-90. https://doi.org/10.1056/NEJMoa051113
  3. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054-61. https://doi.org/10.1016/S0140-6736(05)74230-6
  4. Campbell PJ, Scott LM, Buck G, Wheatley K, East CL, Marsden JT, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 2005;366:1945-53. https://doi.org/10.1016/S0140-6736(05)67785-9
  5. Wolanskyj AP, Lasho TL, Schwager SM, McClure RF, Wadleigh M, Lee SJ, et al. JAK2 mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance. Br J Haematol 2005;131:208-13. https://doi.org/10.1111/j.1365-2141.2005.05764.x
  6. Barosi G, Bergamaschi G, Marchetti M, Vannucchi AM, Guglielmelli P, Antonioli E, et al. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood 2007;110:4030-6. https://doi.org/10.1182/blood-2007-07-099184
  7. Rudzki Z, Sacha T, Stoj A, Czekalska S, Wojcik M, Skotnicki AB, et al. 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. Int J Hematol 2007;86:130-6. https://doi.org/10.1532/IJH97.E0607
  8. De Stefano V, Za T, Rossi E, Vannucchi AM, Ruggeri M, Elli E, et al. Increased risk of recurrent thrombosis in patients with essential thrombocythemia carrying the homozygous JAK2 V617F mutation. Ann Hematol 2010;89:141-6. https://doi.org/10.1007/s00277-009-0788-5
  9. Silver RT, Vandris K, Wang YL, Adriano F, Jones AV, Christos PJ, 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. https://doi.org/10.1016/j.leukres.2010.06.017
  10. Vannucchi AM, Antonioli E, Guglielmelli P, Longo G, Pancrazzi A, Ponziani V, et al. Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden. Leukemia 2007;21:1952-9. https://doi.org/10.1038/sj.leu.2404854
  11. Tefferi A, Lasho TL, Schwager SM, Strand JS, Elliott M, Mesa R, et al. The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera. Cancer 2006;106:631-5. https://doi.org/10.1002/cncr.21645
  12. Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, Marchioli R, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood 2007;110:840-6. https://doi.org/10.1182/blood-2006-12-064287
  13. Passamonti F, Rumi E, Pietra D, Elena C, Boveri E, Arcaini L, 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. https://doi.org/10.1038/leu.2010.148
  14. Tefferi A, Strand JJ, Lasho TL, Knudson RA, Finke CM, Gangat N, et al. Bone marrow JAK2V617F allele burden and clinical correlates in polycythemia vera. Leukemia 2007;21:2074-5. https://doi.org/10.1038/sj.leu.2404724
  15. Antonioli E, Guglielmelli P, Pancrazzi A, Bogani C, Verrucci M, Ponziani V, et al. Clinical implications of the JAK2 V617F mutation in essential thrombocythemia. Leukemia 2005;19:1847-9. https://doi.org/10.1038/sj.leu.2403902
  16. Antonioli E, Guglielmelli P, Poli G, Bogani C, Pancrazzi A, Longo G, et al. Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia. Haematologica 2008;93:41-8. https://doi.org/10.3324/haematol.11653
  17. Guglielmelli P, Barosi G, Specchia G, Rambaldi A, Lo Coco F, Antonioli E, et al. Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele. Blood 2009;114:1477-83. https://doi.org/10.1182/blood-2009-04-216044
  18. Campbell PJ, Griesshammer M, Dohner K, Dohner H, Kusec R, Hasselbalch HC, et al. V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Blood 2006;107:2098-100. https://doi.org/10.1182/blood-2005-08-3395
  19. Delhommeau F, Jeziorowska D, Marzac C, Casadevall N. Molecular aspects of myeloproliferative neoplasms. Int J Hematol 2010;91:165-73. https://doi.org/10.1007/s12185-010-0530-z
  20. Passamonti F, Maffioli M, Caramazza D. New generation small-molecule inhibitors in myeloproliferative neoplasms. Curr Opin Hematol 2012;19:117-23. https://doi.org/10.1097/MOH.0b013e32834ff575
  21. De Stefano V, Rossi E, Za T, Ciminello A, Betti S, Luzzi C, et al. JAK2V617F mutational frequency in essential thrombocythemia associated with splanchnic or cerebral vein thrombosis. Am J Hematol 2011;86:526-8. https://doi.org/10.1002/ajh.22024
  22. Tefferi A, Lasho TL, Schwager SM, Steensma DP, Mesa RA, Li CY, et al. The JAK2(V617F) tyrosine kinase mutation in myelofibrosis with myeloid metaplasia: lineage specificity and clinical correlates. Br J Haematol 2005;131:320-8. https://doi.org/10.1111/j.1365-2141.2005.05776.x
  23. Lasho TL, Mesa R, Gilliland DG, Tefferi A. Mutation studies in CD3+, CD19+ and CD34+ cell fractions in myeloproliferative disorders with homozygous JAK2(V617F) in granulocytes. Br J Haematol 2005;130:797-9. https://doi.org/10.1111/j.1365-2141.2005.05682.x

Cited by

  1. The allele burden of JAK2 V617F can aid in differential diagnosis of Philadelphia Chromosome-Negative Myeloproliferative Neoplasm vol.48, pp.2, 2013, https://doi.org/10.5045/br.2013.48.2.128
  2. Evaluation of clinical and laboratory findings with JAK2 V617F mutation as an independent variable in essential thrombocytosis vol.41, pp.10, 2014, https://doi.org/10.1007/s11033-014-3559-x
  3. Incidence and patient survival of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms in the United States, 2001–12 vol.174, pp.3, 2016, https://doi.org/10.1111/bjh.14061
  4. High frequency of JAK2 exon 12 mutations in Korean patients with polycythaemia vera: novel mutations and clinical significance vol.69, pp.8, 2016, https://doi.org/10.1136/jclinpath-2016-203649
  5. Characterization and Prognosis Significance of JAK2 (V617F), MPL, and CALR Mutations in Philadelphia-Negative Myeloproliferative Neoplasms vol.17, pp.10, 2016, https://doi.org/10.22034/apjcp.2016.17.10.4647
  6. Janus kinase 2 mutations in cases with BCR-ABL-negative chronic myeloproliferative disorders from Turkey vol.7, pp.1, 2017, https://doi.org/10.4103/2231-0770.197511
  7. How ruxolitinib modified the outcome in myelofibrosis: focus on overall survival, allele burden reduction and fibrosis changes vol.10, pp.2, 2012, https://doi.org/10.1080/17474086.2017.1273766
  8. Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population vol.7, pp.4, 2012, https://doi.org/10.3892/br.2017.977
  9. JAK2V617F allele burden: innovative concept in monitoring of myeloproliferative neoplasms vol.11, pp.2, 2012, https://doi.org/10.1007/s12254-018-0397-x
  10. The epidemiology and clinical characteristics of myeloproliferative neoplasms in Malaysia vol.7, pp.None, 2018, https://doi.org/10.1186/s40164-018-0124-7
  11. Evaluation of the JAK2V617F mutational burden in patients with philadelphia chromosome negative myeloproliferative neoplasms: A single-center experience vol.22, pp.2, 2019, https://doi.org/10.2478/bjmg-2019-0021
  12. Relationship of JAK2 (V617F) Allelic Burden with Clinico-Haematological Manifestations of Philadelphia-Negative Myeloproliferative Neoplasms vol.21, pp.9, 2012, https://doi.org/10.31557/apjcp.2020.21.9.2805