Kronik myeloproliferatif neoplazili hastalarda JAK2V617F mutasyon ve tromboemboli durumlarının değerlendirilmesi; Tek Merkez deneyimi

Özet Amaç: Kronik miyeloproliferatif neoplazm (KMPN), hemostaz ve tromboz anomalileri ve akut lösemiye ilerleyebilen klonal bir hastalıktır. polisitemi vera (PV), esansiyel trombositoz (ET) ve idiopatik myelofibrozis (IMF) bcr-abl negatif KMPNlerdir. Gereç ve yöntem: Bu çalışmada 2008-2013 yılları arasında İzmir Bozyaka Eğitim Araştırma Hastanesi hematoloji kliniğinde takip edilen ve bcr-abl negatif kronik myeloproliferatif neoplazi (KMPN) tanısı alan 128 olgu değerlendirildi. Hastaların demografik özellikleri, laboratuar sonuçları, JAK2V617F mutasyon durumları ve kullandığı tedaviler hasta dosyalarından geriye dönük olarak kaydedildi. Bulgular: Hastaların 63ü kadın (%49.2), 65i erkek (%50.8) idi. Yaşları 2387 yaş aralığında ve ortanca yaş 65 idi. 87 hastanın (%68) JAK2V617F mutasyonu pozitif, 41 hastanın (%32) ise JAK2V617F mutasyonu negatif bulundu. JAK2V617F mutasyonu pozitif olan hastaların %42.5inde (37/87), JAK2V617F mutasyonu negatif olan hastaların ise %14.9unda (13/87) trombotik olay saptandı. JAK2 mutasyonu pozitif olan hastalarda trombotik olayların daha sık olması istatiksel olarak anlamlı bulundu (p=0.003). En çok görülen trombotik olayın koroner arter hastalığı olduğu görüldü (20/50). Sonuç: Sonuç olarak, KMPNli hastalarda JAK2V617F gen mutasyonu tanı ve komplikasyonlar için önemli bir bulgudur.

The evaluation of JAK2V617F mutation and thromboembolism in chronic myeloproliferative neoplasia patients; A single center experience

Abstract Purpose: Myeloproliferative neoplasms are clonal diseases associated with hemostasis and thrombosis anomalies and can progress to acute leukemia. Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Idiopathic Myelofibrosis (IMF) are bcr-abl negative myeloproliferative neoplasms. Materials and methods: In this study, the researchers evaluated 128 bcr-abl negative CMPN patients, who were followed in Izmir Bozyaka Traning and Research Hospital, Department of Hematology, between 2008 and 2013. Their demographic features, laboratory results, the state of JAK2V617F mutation and previous treatments were investigated retrospectively. Results: Of the total 128 patients, 63 patients were female and 65 were male. The patients ages were between 23and 87. Median age was sixty five. 87 of patients were JAK2V617F positive. 41 patients were JAK2V617F negative. 37 of the 87 JAK2V617F positive patients (37/87) and 13of the 87 JAK2V617F negative patients (13/87) had thrombotic events. The fact that JAK2V617F mutation positive patients had more thrombotic events was considered clinically and statistically significant (p=0.003). The most commonly seen thrombotic event was coroner artery diseases (20/50). Conclusion: In conclusion, JAK2V617F gene mutation is an important finding for diagnosis and complications of CMPN patients.

PDF

___

1.Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054-1061.
2.Marchetti M, Falanga A. Leukocytosis, JAK2V617F mutation, and hemostasis in myeloproliferative disorders. Pathophysiol Haemos Thromb 2008;36:148-159.
3.Constantinescu SN. A new era for small molecule screening: from new targets, such as JAK2 V617F, to complex cellular screens. J Cell Mol Med 2009;13: 212-214.
4.Yamaoka K, Saharinen P, Pesu M, Holt VE 3rd, Silvennoinen O, OShea JJ. The Janus kinases (Jaks). Genome Biol 2004;5:253-258.
5.Schindler C, Levy DE, Decker T. JAK-STAT signaling: from interferons to cytokines. J Biol Chem 2007;282:20059- 20063.
6.Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program 2009;636- 642.
7.Kristensen DM, Kalisz M, Nielsen JH. Cytokine signalling in embryonic stem cells. APMIS 2005;113:756-772.
8.Mahfouz RA, Hoteit R, Salem Z, et al. JAK2 V617F gene mutation in the laboratory work-up of myeloproliferative disorders: experience of a major referral center in Lebanon. Genet Test Mol Biomarkers 2011;15:263-265.
9.Nielsen C, Birgens HS, Nordestgaard BG, Bojesen SE. Diagnostic value of JAK2 V617F somatic mutation for myeloproliferative cancer in 49 488 individuals from the general population. Br J Haematol 2013;160:70-79.
10.Anand S, Stedham F, Beer P, et al. Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms. Blood 2011;118:177-181.
11. Campell PJ, Gren AR. The myeloproliferative disorders. N Engl J Med 2006;355: 2452-2466.
12. Vannucchi AM. JAK2 Mutation and thrombosis in the myeloproliferative neoplasms Curr Hematology 2010;5:22-28.
13. James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144-1148.
14. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387-397.
15. Campbell PJ, Scott LM, Buck G, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 2005;366:1945-1953.
16. Tefferi A. Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era. Hematology Am Soc Hematol Educ Program 2006:240- 245
17. Hookham MB, Elliott J, Suessmuth Y, et al. The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3. Blood 2007;109:4924-4929.
18. Gruppo Italiano Studio Policitemia: Polycythemia vera. The natural history of 1213 patients followed for 20 years. Ann Intern Med 1995;123:656-664.
19. Ziakas PD. Effect of JAK2 V617F on thrombotic risk in patients with essential thrombocythemia: measuring the uncertain. Haematologica 2008 ;93:1412-1414.
20. Dahabreh IJ, Zoi K, Giannouli S, Zoi C, Loukopoulos D, Voulgarelis M.Is JAK2 V617F mutation more than a diagnostic index? A meta-analysis of clinical outcomes in essential thrombocythemia. Leuk Res 2009;33:67-73.
21. Lussana F, Caberlon S, Pagani C, Kamphuisen PW, Büller HR, Cattaneo M. Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: a systematic review. Thromb Res 2009;124:409-417.