Ann Lab Med.  2012 Nov;32(6):385-391.

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

• Ha JS
• Kim YK
• Jung SI
• Jung HR
• Chung IS

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%+/-24.9%) compared with ET (40.5%+/-25.2%) and PMF patients (31.5%+/-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%+/-23.7%) than patients without organomegaly (35.6%+/-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.

Keyword

Janus kinase 2; Allele; Myeloproliferative neoplasm

MeSH Terms

Adult
Age Factors
Aged
Alleles
Female
Hematocrit
Hemoglobins/metabolism
Humans
Janus Kinase 2/*genetics
Leukocyte Count
Male
Middle Aged
Myeloproliferative Disorders/*genetics/pathology
Polycythemia Vera/genetics
Polymorphism, Single Nucleotide
Primary Myelofibrosis/genetics
Thrombocythemia, Essential/genetics
Hemoglobins
Janus Kinase 2

Reference

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. 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. 352:1779–1790.

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. 365:1054–1061.

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. 366:1945–1953.

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. 131:208–213.

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. 110:4030–4036.

7. Rudzki Z, Sacha T, Stój A, Czekalska S, Wójcik 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. 86:130–136.

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. 89:141–146.

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. 35:177–182.

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. 21:1952–1959.

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. 106:631–635.

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. 110:840–846.

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. 24:1574–1579.

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. 21:2074–2075.

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. 19:1847–1849.

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. 93:41–48.

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. 114:1477–1483.

18. Campbell PJ, Griesshammer M, Döhner K, Döhner H, Kusec R, Hasselbalch HC, et al. V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Blood. 2006. 107:2098–2100.

19. Delhommeau F, Jeziorowska D, Marzac C, Casadevall N. Molecular aspects of myeloproliferative neoplasms. Int J Hematol. 2010. 91:165–173.

20. Passamonti F, Maffioli M, Caramazza D. New generation small-molecule inhibitors in myeloproliferative neoplasms. Curr Opin Hematol. 2012. 19:117–123.

21. De Stefano V, Rossi E, Za T, Ciminello A, Betti S, Luzzi C, et al. JAK2 V617F mutational frequency in essential thrombocythemia associated with splanchnic or cerebral vein thrombosis. Am J Hematol. 2011. 86:526–528.

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. 131:320–328.

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. 130:797–799.