COMPARISON OF PATIENTS WITH PRE-DIAGNOSIS OF MYELOPROLIFERATIVE NEOPLASM PATIENTS WITH LOW AND HIGH JAK2V617F ALLELE BURDEN IN TERMS OF CLINICAL AND HEMATOLOGICAL PARAMETERS

Yıl 2024, , 76 - 80, 17.01.2024

Özgür Erkal , Barış Paksoy , Püsem Patır

https://doi.org/10.18229/kocatepetip.1254047

Öz

OBJECTIVE: JAK2V617F mutation positivity is the main criterion for the diagnosis of chronic myeloproliferative neoplasms (CMPN). Determination of allele burden has become a standard diagnostic procedure in most molecular laboratories, but no cutoff value is specified for the diagnosis of CMPN. Herein, comparison of myeloproliferative neoplasia prediagnosed patients with low and high JAK2V617F allele burden in terms of clinical and hematological parameters were aimed.
MATERIAL AND METHODS: Ninty-five patients with positive JAK2V617F mutation in the Medical Genetics Clinic of Health Sciences University Antalya Training and Research Hospital between 2019-2021 were analyzed retrospectively.
RESULTS: Sixty four percent of 46 patients with low allele burden (≤3%) had the CMPN phenotype, while 100% of 49 patients with high allele burden (>3%) had the CMPN phenotype. There was no statistically significant difference between the two groups in terms of erythrocyte count, hemoglobin level, and mean erythrocyte volumes, however leukocyte, neutrophil and platelet elevations were found to be statistically significant in favor of the group with JAK2V617F allele burden >3% (p=0.007; p<0.001; p<0.001).
CONCLUSIONS: Although the low allele burden JAK2V617F mutation is difficult to interpret in daily clinical practice, not all positive patients have a hematological diagnosis. All patients with an allele burden >3% were diagnosed with CMPN; therefore, an allele burden above this limit can be considered as an indicator of the presence of a myeloproliferative disease. Studies with larger patient cohorts prospectively examined using standardized molecular methods are needed to define the approach to the low allele burden JAK2V617F mutation.

Anahtar Kelimeler

Myeloproliferative disorders, JAK2 protein, Alleles

DÜŞÜK VE YÜKSEK JAK2V617F ALLEL YÜKÜ OLAN MİYELOPROLİFERATİF NEOPLAZİ ÖN TANILI HASTALARIN KLİNİK VE HEMATOLOJİK PARAMETRELER AÇISINDAN KARŞILAŞTIRILMASI

Öz

AMAÇ: JAK2V617F mutasyonu pozitifliği kronik miyeloproliferatif neoplazilerin (KMPN) tanısı için ana kriterdir. Mutasyon yükünün belirlenmesi çoğu moleküler laboratuvarda standart bir tanı prosedürü haline gelmiştir, ancak KMPN tanısı için bir sınır değer belirtilmemektedir. Burada, JAK2V617F mutasyon yükü düşük ve yüksek olan miyeloproliferatif neoplazi ön tanılı hastaların klinik ve hematolojik parametreler açısından karşılaştırılması amaçlandı.
GEREÇ VE YÖNTEM: Sağlık Bilimleri Üniversitesi Antalya Eğitim ve Araştırma Hastanesi tıbbi genetik kliniğinde 2019 - 2021 yılları arasında JAK2V617F mutasyonu pozitif olan 95 hasta retrospektif olarak analiz edildi.
BULGULAR: Allel yükü düşük (≤%3) olan 46 hastanın %64'ü KMPN fenotipine sahipken, yüksek allel yükü (>%3) olan 49 hastanın %100'ü KMPN fenotipine sahipti. Her iki grup arasında eritrosit sayısı, hemoglobin düzeyi, ortalama eritrosit hacimleri arasında istatistiksel bir fark bulunmazken; lökosit, nötrofil ve trombosit yüksekliği JAK2V617F allel yükü >%3 olan grup lehine istatistiksel olarak anlamlı bulundu (p=0.007; p<0.001; p<0.001).
SONUÇ: Düşük allel yüklü JAK2V617F mutasyonunun günlük klinik uygulamada yorumlanması zor olmakla birlikte tüm pozitif hastalara hematolojik tanı konmamıştır. Allel yükü >%3 olan tüm hastalara KMPN tanısı konulmuştur; bu nedenle, bu sınırın üzerindeki bir mutasyon yükü, miyeloproliferatif bir hastalığın varlığın göstergesi olarak kabul edilebilir. Düşük allel yüklü JAK2V617F mutasyonuna yaklaşımı tanımlamak için standardize edilmiş moleküler yöntemlerle prospektif olarak incelenen daha büyük hasta gruplarına sahip çalışmalara ihtiyaç vardır.

Anahtar Kelimeler

Miyeloproliferatif bozukluklar, JAK2 protein, Alleller

Kaynakça

• 1. Tefferi A, 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.
• 2. Wang YL, Vandris K, Jones A, et al. JAK2 Mutations are present in all cases of polycythemia vera. Leukemia. 2008;22:1289.
• 3. Lippert E, Boissinot M, Kralovics R, et al. The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. Blood. 2006;108:1865–7.
• 4. Tiedt R, Hao-Shen H, Sobas MA, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood. 2008;111:3931–40.
• 5. Levine RL. JAK2V617F: you can't have too much. Blood. 2008;111(8):3913.
• 6. Scott LM, Campbell PJ, Baxter EJ, 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.
• 7. Steensma DP, Dewald GW, Lasho TL, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes. Blood. 2005;106:1207–9.
• 8. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391–405.
• 9. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379–90.
• 10. Jelinek J, Oki Y, Gharibyan V, et al. JAK2 mutation 1849G > T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia. Blood. 2005;106:3370– 3.
• 11. Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005;106:2162–8.
• 12. Boissinot M, Garand R, Hamidou M, et al. The JAK2-V617F mutation and essential thrombocythemia features in a subset of patients with refractory anemia with ring sideroblasts (RARS). Blood. 2006;108:1781–2.
• 13. Ohyashiki K, Aota Y, Akahane D, et al. The JAK2 V617F tyrosine kinase mutation in myelodysplastic syndromes (MDS) developing myelofibrosis indicates the myeloproliferative nature in a subset of MDS patients. Leukemia. 2005;19:2359–60.
• 14. Boissinot M, Lippert E, Girodon F, et al. Latent myeloproliferative disorder revealed by the JAK2-V617F mutation and endogenous megakaryocytic colonies in patients with splanchnic vein thrombosis. Blood. 2006;108:3223–4.
• 15. Wang SA, Hasserjian RP, Loew JM, et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis harbors JAK2 mutation and shows overlapping myeloproliferative and myelodysplastic features. Leukemia. 2006;20:1641–4.
• 16. Zhao S, Zhang X, Xu Y, 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.
• 17. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110:840–6.
• 18. Antonioli E, Guglielmelli P, Poli G, et al. Myeloproliferative Disorders Research Consortium (MPD-RC). Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia. Haematologica. 2008;93:41–8.
• 19. Lussana F, Caberlon S, Pagani C, et al. Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: a systematic review. Thrombosis research. 2009;124:409–17.
• 20. De Stefano V, Za T, Rossi E, et al. Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica. 2008;93:372–80.
• 21. Barbui T, Finazzi G, Carobbio A, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis) Blood. 2012;120:5128–33.
• 22. Tefferi A, Lasho TL, Huang J, et al. Low JAK2V617F allele burden in primary myelofibrosis, compared to either a higher allele burden or unmutated status, is associated with inferior overall and leukemia-free survival. Leukemia. 2008;22:756–61.
• 23. Guglielmelli P, Barosi G, Specchia G, et al. Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele. Blood. 2009;114:1477–83.
• 24. Campbell PJ, Baxter EJ, Beer PA, et al. Mutation of JAK2 in the myeloproliferative disorders: timing, clonality studies, cytogenetic associations, and role in leukemic transformation. Blood. 2006;108:3548–55.
• 25. Bench AJ, White HE, Foroni L, et al. British Committee for Standards in Haematology. Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the detection of JAK2 V617F and other relevant mutations. Br J Haematol. 2013;160:25–34.
• 26. Jovanovic JV, Ivey A, Vannucchi AM, et al. Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study. Leukemia. 2013;27:2032–9.
• 27. Lippert E, Girodon F, Hammond E, et al. Concordance of assays designed for the quantification of JAK2V617F: a multicenter study. Haematologica. 2009;94:38–45.
• 28. Mason J, Akiki S, Griffiths MJ. Pitfalls in molecular diagnosis in haemato-oncology. J Clin Pathol. 2011;64:275–8.
• 29. McClure R, Mai M, Lasho T. Validation of two clinically useful assays for evaluation of JAK2 V617F mutation in chronic myeloproliferative disorders. Leukemia. 2006;20:168–71.
• 30. Campbell PJ, Scott LM, Baxter EJ, et al. Methods for the detection of the JAK2 V617F mutation in human myeloproliferative disorders. Methods Mol Med. 2006;125:253–64.
• 31. Cankovic M, Whiteley L, Hawley RC, et al. Clinical performance of JAK2 V617F mutation detection assays in a molecular diagnostics laboratory: evaluation of screening and quantitation methods. Am J Clin Pathol. 2009;132:713–21.
• 32. Martinaud C, Brisou P, Mozziconacci MJ. Is the JAK2(V617F) mutation detectable in healthy volunteers?. Am J Hematol. 2010;85:287–8.
• 33. Sidon P, Housni H El, Dessars B, et al. The JAK2V617F mutation is detectable at very low level in peripheral blood of healthy donors. Leukemia. 2006;20:1622.
• 34. Xu X, Zhang Q, Luo J, et al. Prevalence in a large Chinese hospital population. Blood. 2007;109:339–42.
• 35. Nielsen C, Birgens HS, Nordestgaard BG, et al. Diagnostic value of JAK2 V617F somatic mutation for myeloproliferative cancer in 49 488 individuals from the general population. Br J Haematol. 2013;160(1):70–9.
• 36. Rapado I, Albizua E, Ayala R, et al. Validity test study of JAK2 V617F and allele burden quantification in the diagnosis of myeloproliferative diseases. Ann Hematol. 2008;87:741–9.
• 37. Passamonti F, Rumi E, Pietra D, et al. JAK2 (V617F) mutation in healthy individuals. Br J Haematol. 2007;136:678–9.
• 38. Lippert E, Mansier O, Migeon M, et al. Clinical and biological characterization of patients with low (0.1-2%) JAK2V617F allele burden at diagnosis. Haematologica. 2014;99:e98–101.
• 39. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9-16.
• 40. He ZP, Tian HY, Tan M, et al. Clinical Analysis of Driver Mutation in Patients with Ph Negative Myeloproliferative Neoplasms. J Exp Hematol. 2018;26(3):842–8.
• 41. Tefferi A, Guglielmelli P, Larson DR, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014;124(16):2507–13.
• 42. Rumi E, Pietra D, Pascutto C, et al. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood. 2014;124(7):1062–9.