Influence of JAK2V617F allele burden on clinical phenotype of polycythemia vera patients: A study from India

Sudha Sazawal; Kanwaljeet Singh; Sunita Chhikara; Rekha Chaubey; Manoranjan Mahapatra; Renu Saxena

doi:10.4103/sajc.sajc_161_18

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ORIGINAL ARTICLE: Hematolymphoid Malignancies

08 (

); 127-129

doi:

10.4103/sajc.sajc_161_18

Influence of JAK2V617F allele burden on clinical phenotype of polycythemia vera patients: A study from India

Sudha Sazawal^1,, Kanwaljeet Singh¹, Sunita Chhikara¹, Rekha Chaubey¹, Manoranjan Mahapatra¹, Renu Saxena¹

1 Department of Hematology, All India Institute of Medical Sciences, New Delhi

*Corresponding author: Dr. Sudha Sazawal. sudha_sazawal@hotmail.com

Published: 2020-12-21

MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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Abstract

Background: Elevated JAK2V617F allele burden is associated with enhanced expression of downstream target genes in Philadelphia negative chronic myeloproliferative neoplasms (CMPNs) which include PV, ET & PMF. Previous studies have shown the impact of JAK2V617F allele burden on clinical phenotype of CMPNs. However, there is no data from India regarding the association between JAK2V617F allele burden and clinical phenotype in PV. Aims/Settings and Design: We aimed to investigate the effect of allele burden on clinical phenotype in 90 JAK2V617F positive PV patients and to see its influence on disease related complications. Material and Methods: Allele burden of 90 JAK2V617F positive PV patients was quantified by Real-time polymerase chain reaction (RQ-PCR). Results: 74/90 (82.22%) were males and 16/90 (17.78%) were females (median 45 years, range 35-78). Patients with age >50 years had significantly higher JAK2V617F allele burden (median 40.15%, range 0.49–91.62 %) than patients with ≤ 50 years age (median 48.59 %, range 0.56–86.74 %; P < 0.032). Patients with splenomegaly had significantly higher JAK2V617F allele burden (mean 50.24%, range 6.91–84.17%) than patients without splenomegaly (mean 33.82 %, range 0.49–71.83 %; P < 0.017). Patients with higher allele burden (median 57.20, range 43.4–72.03%) had significantly raised thrombotic events than the patients with lower allele burden (median 37.38, range 0.49–84.17% P < 0.043). 49/90 (54%) were homozygous and 41/90 (46%) were heterozygous. Conclusions: Higher JAK2V617F allele burden showed association with increased age, splenomegaly and thrombotic events. Thus, it may be considered for prognostication and setting up the treatment protocol in PV patients.

Keywords

Acknowledgment

The authors wish to acknowledge Mr. Rajender Chhoker and Mr. Arun Dalsus for technical assistance.

References

James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia Vera. Nature 2005;434:1144-8.
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.
Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, 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, 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.
Larsen TS, Pallisgaard N, Møller MB, Hasselbalch HC. The JAK2 V617F allele burden in essential thrombocythemia, polycythemia vera and primary myelofibrosis – Impact on disease phenotype. Eur J Haematol 2007;79:508-15.
Campbell PJ, Baxter EJ, Beer PA, Scott LM, Bench AJ, Huntly BJ, et al. Mutation of JAK2 in the myeloproliferative disorders: Timing, clonality studies, cytogenetic associations, and role in leukemic transformation. Blood 2006;108:3548-55.
Kralovics R, Teo SS, Buser AS, Brutsche M, Tiedt R, Tichelli A, et al. Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of JAK2. Blood 2005;106:3374-6.
Tefferi A, Sirhan S, Lasho TL, Schwager SM, Li CY, Dingli D, et al. Concomitant neutrophil JAK2 mutation screening and PRV-1 expression analysis in myeloproliferative disorders and secondary polycythaemia. Br J Haematol 2005;131:166-71.
Lippert E, Boissinot M, Kralovics R, Girodon F, Dobo I, Praloran V, et al. The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. Blood 2006;108:1865-7.
Passamonti F, Rumi E, Pietra D, Della Porta MG, Boveri E, Pascutto C, et al. Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+cells into peripheral blood in myeloproliferative disorders. Blood 2006;107:3676-82.
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.
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.
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.
Cheung B, Radia D, Pantelidis P, Yadegarfar G, Harrison C. The presence of the JAK2 V617F mutation is associated with a higher haemoglobin and increased risk of thrombosis in essential thrombocythaemia. Br J Haematol 2006;132:244-5.
Finazzi G, Rambaldi A, Guerini V, Carobbo A, Barbui T. Risk of thrombosis in patients with essential thrombocythemia and polycythemia vera according to JAK2 V617F mutation status. Haematologica 2007;92:135-6.
Sazawal S, Bajaj J, Chikkara S, Jain S, Bhargava R, Mahapatra M, et al. Prevalence of JAK2 V617F mutation in Indian patients with chronic myeloproliferative disorders. Indian J Med Res 2010;132:423-7.
Singh N, Sazawal S, Upadhyay A, Chhikara S, Mahapatra M, Saxena R, et al. Correlation of JAK2V617F mutational status in primary myelofibrosis with clinico-hematologic characteristics and international prognostic scoring system scoring: A single center experience. Indian J Pathol Microbiol 2015;58:187-91.
Scott LM, Campbell PJ, Baxter EJ, Todd T, Stephens P, Edkins S, et al. The V617F JAK2 mutation is uncommon in cancers and in myeloid malignancies other than the classic myeloproliferative disorders. Blood 2005;106:2920-1.
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.
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.
Zhao S, Zhang X, Xu Y, Feng Y, Sheng W, Cen J, et al. Impact of JAK2V617F mutation burden on disease phenotype in Chinese patients with JAK2V617F-positive polycythemia vera (PV) and essential thrombocythemia (ET). Int J Med Sci 2016;13:85-91.
Vannucchi AM. JAK2 mutation and thrombosis in the myeloproliferative neoplasms. Curr Hematol Malig Rep 2010;5:22-8.

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[1] James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia Vera. Nature 2005;434:1144-8.

[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.

[3] Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, 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.

[4] 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.

[5] Larsen TS, Pallisgaard N, Møller MB, Hasselbalch HC. The JAK2 V617F allele burden in essential thrombocythemia, polycythemia vera and primary myelofibrosis – Impact on disease phenotype. Eur J Haematol 2007;79:508-15.

[6] Campbell PJ, Baxter EJ, Beer PA, Scott LM, Bench AJ, Huntly BJ, et al. Mutation of JAK2 in the myeloproliferative disorders: Timing, clonality studies, cytogenetic associations, and role in leukemic transformation. Blood 2006;108:3548-55.

[7] Kralovics R, Teo SS, Buser AS, Brutsche M, Tiedt R, Tichelli A, et al. Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of JAK2. Blood 2005;106:3374-6.

[8] Tefferi A, Sirhan S, Lasho TL, Schwager SM, Li CY, Dingli D, et al. Concomitant neutrophil JAK2 mutation screening and PRV-1 expression analysis in myeloproliferative disorders and secondary polycythaemia. Br J Haematol 2005;131:166-71.

[9] Lippert E, Boissinot M, Kralovics R, Girodon F, Dobo I, Praloran V, et al. The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. Blood 2006;108:1865-7.

[10] Passamonti F, Rumi E, Pietra D, Della Porta MG, Boveri E, Pascutto C, et al. Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+cells into peripheral blood in myeloproliferative disorders. Blood 2006;107:3676-82.

[11] 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.

[12] 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.

[13] 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.

[14] Cheung B, Radia D, Pantelidis P, Yadegarfar G, Harrison C. The presence of the JAK2 V617F mutation is associated with a higher haemoglobin and increased risk of thrombosis in essential thrombocythaemia. Br J Haematol 2006;132:244-5.

[15] Finazzi G, Rambaldi A, Guerini V, Carobbo A, Barbui T. Risk of thrombosis in patients with essential thrombocythemia and polycythemia vera according to JAK2 V617F mutation status. Haematologica 2007;92:135-6.

[16] Sazawal S, Bajaj J, Chikkara S, Jain S, Bhargava R, Mahapatra M, et al. Prevalence of JAK2 V617F mutation in Indian patients with chronic myeloproliferative disorders. Indian J Med Res 2010;132:423-7.

[17] Singh N, Sazawal S, Upadhyay A, Chhikara S, Mahapatra M, Saxena R, et al. Correlation of JAK2V617F mutational status in primary myelofibrosis with clinico-hematologic characteristics and international prognostic scoring system scoring: A single center experience. Indian J Pathol Microbiol 2015;58:187-91.

[18] Scott LM, Campbell PJ, Baxter EJ, Todd T, Stephens P, Edkins S, et al. The V617F JAK2 mutation is uncommon in cancers and in myeloid malignancies other than the classic myeloproliferative disorders. Blood 2005;106:2920-1.

[19] 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.

[20] 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.

[21] Zhao S, Zhang X, Xu Y, Feng Y, Sheng W, Cen J, et al. Impact of JAK2V617F mutation burden on disease phenotype in Chinese patients with JAK2V617F-positive polycythemia vera (PV) and essential thrombocythemia (ET). Int J Med Sci 2016;13:85-91.

[22] Vannucchi AM. JAK2 mutation and thrombosis in the myeloproliferative neoplasms. Curr Hematol Malig Rep 2010;5:22-8.

Influence of JAK2V617F allele burden on clinical phenotype of polycythemia vera patients: A study from India

Abstract

Abstract

Keywords

Acknowledgment

References

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