The ipsogen JAK2 MutaQuant Kit is an in vitro quantitative test intended for the detection and quantification of JAK2 V617F/G1849T allele in genomic DNA extracted from peripheral blood of subjects with suspected myeloproliferative neoplasm (MPN).
The absence of the JAK2 V617F/G1849T mutation does not exclude the presence of other JAK2 mutations. The test can report false negative results in case of additional mutations located in nucleotides 88504 to 88622.
A recurrent somatic mutation, V617F, affecting the Janus tyrosine kinase 2 (JAK2) gene, has been identified in 2005 2–5, leading to a major breakthrough in the understanding, classification, and diagnosis of myeloproliferative neoplasms (MPN). JAK2 is a critical intracellular signalling molecule for a number of cytokines, including erythropoietin.
The JAK2 V617F mutation is detected in >95% of patients with polycythemia vera (PV), 50–60% of patients with essential thrombocythemia (ET), and in 50% of patients with primary myelofibrosis (PMF). JAK2 V617F has been also detected in some rare cases of chronic myelomonocytic leukaemia, myelodysplasic syndrome, systemic mastocytosis, and chronic neutrophilic leukaemia, but in 0% of CML6.
The mutation corresponds to a single-nucleotide change of JAK2 nucleotide 1849 in exon 14, resulting in a unique valine (V) to phenylalanine (F) substitution at position 617 of the protein (JH2 domain). It leads to constitutive activation of JAK2, hematopoietic transformation in vitro, and erythropoietin-independent erythroid colony (EEC) growth in all patients with PV and a large proportion of ET and PMF patients7. JAK2 V617F represents a key driver in the transformation of hematopoietic cells in MPN, but the exact pathological mechanisms leading, with the same unique mutation, to such different clinical and biological entities remain to be fully elucidated.
Traditionally, the diagnosis of MPNs was based on clinical, bone marrow histology and cytogenetic criteria. The discovery of a disease-specific molecular marker resulted in both simplification of the process and increased diagnostic accuracy. Detection of the JAK2 V617F mutation is now part of the reference WHO 2008 criteria for the diagnosis of BCR-ABL negative MPN, and presence of this mutation is a major criterion for diagnostic confirmation.
Recently, international experts have proposed criteria for therapeutic trials in PV and ET. Based on data on allograft, alpha-interferon, or hydroxyurea, JAK2V617F quantification has been incorporated as a potentially useful tool to monitor treatment response9. A decrease in JAK2 V617F burden has been observed in response to some of the new anti-JAK2 targeted drugs in clinical development10.
1. National Center for Biotechnology Information (NCBI): NT_008413
2. James, C. et al. (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythemia vera. Nature 434, 1144.
3. Levine, R.L. et al. (2005) activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia and myeloid metaplasia with myelofibrosis. Cancer Cell 7, 387.
4. Kralovics, R. et al. (2005) A gain-of-function mutation in JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779.
5. Baxter, E.J. et al. (2005) Acquired mutation in the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 36, 1054.
6. Tefferi, A. et al. (2009) Myeloproliferative neoplasms: contemporary diagnosis using histology and genetics. Nat. Rev. Clin. Oncol. 6, 627.
7. Prchal, J.F. and Axelrad, A.A. (1974) Bone marrow responses in polycythemia vera. N. Engl. J. Med. 290, 1382.
8. Tefferi. A. and Vardiman, J.W. (2008) Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 22, 14.
9. Barosi, G. et al. (2009) Responsive criteria for essential thrombocythemia and polycuthemia vera: result of a European LeukemiaNet consensus conference. Blood 113, 4829.
10. Pardanani, A. et al. (2011) Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J. Clin. Oncol. 29, 789.
11. Lippert, E. et al. (2006) the JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. Blood 108, 1865.
NB This test was introduced afer our DAkkS audit and is therefore not accredited by DAkkS