Epidemiology evaluation of common mutations in JAK2 exon 12 protein in patients with Idiopathic Erythrocythosis

Document Type : Original article

Authors

1 1. MD, Associate Professor of Pathology, Department of Hematology and Blood Bank, Cancer Molecular Pathology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 MSC, Instructor of hematology, Paramedical of Kermanshah University, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran

3 MD, Associate Professor of hematology, Department of Internal Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Msc, Cancer Molecular Pathology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Introduction: Primary erythrocytosis caused defect in progenitor stem cells and this cells became too sensitive to erythropoietin.  The most of acquisitive defect is JAK2V617F mutation that observed in 95% of Polycythemia Vera. This mutation was occurred in exon 14 of JAK2 protein. Other mutations accompany with erythrocytosis is JAK2 exon 12 mutations. The number of this mutations is high. In this study we were survey incident four common mutations in exon 12 of JAK2 protein in Mashhad city.
Materials and Methods: 146 patients with Idiopathic Erythrocytosis practiced in cross section study. Patients DNA was screen for F537-K539delinsL, K539L, H538QK539L and N542-E543del mutations by using ARMS-PCR. To detect PCR production has used 2% agarose gel.
Results: Among four mutations of JAK2 exon 12, just observed N542-E543del in two patients (on male, one female). The mean age of patients with N542E543del mutation was 36±19.79 years and patients with N542E543del negative was 44.62±18.88 years.
Conclusion: The result of this study demonstrated that JAK2 exon 12 mutations isn’t a common abnormality in IE patients. To provide more comprehensive report in IE patients, recommended to investigate JAK2 exon12 mutations in large sample size of IE patients or it is suggested DNA sequencing instead of ARMS-PCR.

Keywords

References

 
1.         Percy MLJ. Genetically heterogeneous origins of idiopathic erythrocytosis. Hematology. 2007;12(2):131-9.
2.         Percy MJ, Scott LM, Erber WN, Harrison CN, Reilly JT, Jones FG, et al. The frequency of JAK2 exon 12 mutations in idiopathic erythrocytosis patients with low serum erythropoietin levels. Haematologica. 2007;92(12):1607-14.
3.         Lasho TL, Pardanani A, Tefferi A. LNK mutations in JAK2 mutation–negative erythrocytosis. New England Journal of Medicine. 2010;363(12):1189-90.
4.         Cario H, Frances McMullin M, Bento C, Pospisilova D, Percy MJ, Hussein K, et al. Erythrocytosis in children and adolescents—classification, characterization, and consensus recommendations for the diagnostic approach. Pediatric blood & cancer. 2013;60(11):1734-8.
5.         Percy MJ, Zhao Q, Flores A, Harrison C, Lappin TR, Maxwell PH, et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(3):654-9.
6.         Pastore YD, Jelinek J, Ang S, Guan Y, Liu E, Jedlickova K, et al. Mutations in the VHL gene in sporadic apparently congenital polycythemia. Blood. 2003;101(4):1591-5.
7.         Gäbler K, Behrmann I, Haan C. JAK2 mutants (eg, JAK2V617F) and their importance as drug targets in myeloproliferative neoplasms. JAK-STAT. 2013;2(3).
8.         Reuther GW. JAK2 activation in myeloproliferative neoplasms. Cell Cycle. 2008;7(6):714-9.
9.         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< i> JAK2 V617F mutation status: a prospective study. The Lancet. 2005;366(9501):1945-53.
10.       Neet K, Hunter T. Vertebrate non-receptor protein-tyrosine kinase families. Genes to Cells. 1996;1(2):147-69.
11.       Orr DW, Patel R, Lea N, Westbrook R, O’GRADY J, Heaton N, et al. The prevalence of the activating JAK2 tyrosine kinase mutation in chronic porto‐splenomesenteric venous thrombosis. Alimentary pharmacology & therapeutics. 2010;31(12):1330-6.
12.       Williams JJ, Munro K, Palmer TM. Role of Ubiquitylation in Controlling Suppressor of Cytokine Signalling 3 (SOCS3) Function and Expression. Cells. 2014;3(2):546-62.
13.       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(6):1865-7.
14.       Zaleskas VM, Krause DS, Lazarides K, Patel N, Hu Y, Li S, et al. Molecular pathogenesis and therapy of polycythemia induced in mice by JAK2 V617F. PloS one. 2006;1(1):e18-e.
15.       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 Journal of Medical Research. 2010;132(4):423.
16.       Meier C, Hoeller S, Bourgau C, Hirschmann P, Schwaller J, Went P, et al. Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas. Modern Pathology. 2009;22(3):476-87.
17.       Bercovich D, Ganmore I, Scott LM, Wainreb G, Birger Y, Elimelech A, et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. The Lancet. 2008;372(9648):1484-92.
18.       Alshemmari SH, Rajaan R, Ameen R, Al-Drees MA, Almosailleakh MR. JAK2V617F allele burden in patients with myeloproliferative neoplasms. Annals of hematology. 2013:1-6.
19.       Pieri L, Pancrazzi A, Pacilli A, Rabuzzi C, Rotunno G, Fanelli T, et al. JAK2V617F complete molecular remission in polycythemia vera/essential thrombocythemia patients treated with ruxolitinib. Blood. 2015;125(21):3352.
20.       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. The Lancet. 2005;365(9464):1054-61.
21.       Scott LM. The JAK2 exon 12 mutations: a comprehensive review. American journal of hematology. 2011;86(8):668-76.
22.       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.
23.       Cazzola M. Somatic mutations of JAK2 exon 12 as a molecular basis of erythrocytosis. Haematologica. 2007;92(12):1585-9.
24.       Semenza GL. Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. Blood. 2009;114(10):2015-9.
25.       Rives S, Pahl HL, Florensa L, Bellosillo B, Neusuess A, Estella J, et al. Molecular genetic analyses in familial and sporadic congenital primary erythrocytosis. haematologica. 2007;92(5):674-7.
26.       Vannucchi AM, Antonioli E, Guglielmelli P, Pancrazzi A, Guerini V, Barosi G, et al. Characteristics and clinical correlates of MPL 515W> L/K mutation in essential thrombocythemia. Blood. 2008;112(3):844-7.
27.       Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930-5.
28.       Lorsbach R, Moore J, Mathew S, Raimondi S, Mukatira S, Downing J. TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t (10; 11)(q22; q23). Leukemia. 2003;17(3):637-41.
29.       Tefferi A, Pardanani A, Lim K, Abdel-Wahab O, Lasho T, Patel J, et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia. 2009;23(5):905-11.
30.       Tefferi A, Lim K-H, Levine R. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;361(11):1117.
31.       Tefferi A, Levine R, Lim K, Abdel-Wahab O, Lasho T, Patel J, et al. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia. 2009;23(5):900-4.
32.       Viguie F, Aboura A, Bouscary D, Ramond S, Delmer A, Tachdjian G, et al. Common 4q24 deletion in four cases of hematopoietic malignancy: early stem cell involvement? Leukemia. 2005;19(8):1411-5.
33.       Martínez-Avilés L, Besses C, Álvarez-Larrán A, Cervantes F, Hernández-Boluda JC, Bellosillo B. JAK2 exon 12 mutations in polycythemia vera or idiopathic erythrocytosis. Haematologica. 2007;92(12):1717-8.
34.       Butcher C, Hahn U, To L, Gecz J, Wilkins E, Scott H, et al. Two novel JAK2 exon 12 mutations in JAK2V617F-negative polycythaemia vera patients. Leukemia. 2008;22(4):870-3.
35.       Poopak B, Farshdousti Hagh M, Saki N, Elahi F, Rezvani H, Khosravipour G, et al. JAK2 V617F mutation in Iranian patients with myeloproliferative neoplasms: clinical and laboratory findings. Turkish Journal of Medical Sciences. 2013;43(3):347-53.
36.       Karimzadeh P, Ghaffari S, Chahardouli B, Zaghal A, Einollahi N, Mousavi S, et al. Evaluation of JAK2V617F mutation prevalence in myeloproliferative neoplasm by AS-RT-PCR. Iranian journal of Pediatric Hematology Oncology. 2011;1(2):38-42.
37.       Schnittger S, Bacher U, Kern W, Schröder M, Haferlach T, Schoch C. Report on two novel nucleotide exchanges in the JAK2 pseudokinase domain: D620E and E627E. Leukemia. 2006;20(12):2195-7.

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