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JAK2 46/1 haplotype analysis in myeloproliferative neoplasms and acute myeloid leukemia

Leukemia volume 24, pages 1809–1813 (2010)Cite this article

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Somatic gain-of-function mutation of the Janus kinase (JAK2) gene (NM_004972.2: c.1849G>T transversion resulting in V617F) has been identified in BCR–ABL-negative chronic myeloproliferative neoplasms (MPNs) (in >95% of polycythaemia vera (PV), and in 40–60% of essential thrombocythaemia (ET) and primary myelofibrosis (PMF)). The inherited genetic background of an individual patient has been long predicted to influence disease susceptibility and phenotype in MPN. Recent studies have demonstrated that the presence of JAK2 V617F is associated with an inherited JAK2 haplotype designated as ‘46/1’ haplotype.1, 2, 3 Carriers of the 46/1 haplotype have higher risk of acquiring JAK2 V617F mutation, but the role of 46/1 haplotype as a predisposition factor for V617F-negative MPN is still remained controversial. Only a few studies4, 5 investigated the potential role of the 46/1 haplotype as a MPN phenotype modifier in the context of the frequency of complications affecting life expectancy, such as thrombosis and myelofibrotic or leukaemic transformation. To extend these observations, the aims of our study were the following: (a) to examine and confirm associations of MPN and the presence of the JAK2 46/1 haplotype in Hungarian V617F-positive and -negative MPN patients; (b) to examine associations of the 46/1 haplotype with distinct clinical characteristics of MPN, (c) to test the haplotype frequency among JAK2 V617F-negative acute myeloid leukemia (AML) patients.

JAK2 rs12343867 SNP tagging 46/1 haplotype (NM_004972.2: c.1864+404A>T) were genotyped in 312 MPN-patients (132 males/180 females; median age of disease onset of 60 years (range: 16–87 years)), 339 patients with AML (158 males/181 females; median age of disease onset of 51 years (range: 16–93 years)) and in 331 Hungarian local controls (196 males/135 females; median age of 41 years (range: 19–76 years)) by LightCycler technology applying melting curve analysis with hybridization probe detection format. C allele frequency and 95% confidence interval (CI) of rs12343867 is presented as 46/1 haplotype frequency. JAK2 V617F mutation detection was performed before the JAK2 rs12343867 genotyping in all patients. JAK2 V617F mutation-negative PV cases, and V617F-positive AML cases were not included in the MPN or AML groups, respectively. As archived germline tissue was not available in our MPN study population, an alternative method (617F- and 617V-specific amplification of JAK2 alleles) was applied. The 617V-specific amplification in V617F-positive cases allowed the detection of the V617F-non-affected allele in heterozygous cases. Appropriate negative controls (JAK2 V617F-negative samples in 617F and homozygous V617F HEL cell line DNA in 617V-specific amplification) were included in each PCR round.

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Acknowledgements

This work was supported by grants from OTKA (K69102) and KMOP 1.1.2-07/1-2008-0003.

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  1. H Andrikovics and S Nahajevszky: These authors contributed equally as first authors.

Authors and Affiliations

  1. Laboratory of Molecular Diagnostics, Hungarian Blood Transfusion Service, Budapest, Hungary

    H Andrikovics, M Koszarska, N Meggyesi, A Bors & A Tordai

  2. Depatment of Haematology and Stem Cell Transplantation, St Istvan and St Laszlo Hospital, Budapest, Hungary

    S Nahajevszky, G Halm, S Lueff, N Lovas, Z Matrai, J Csomor, R Rasonyi, G Mikala, A Sipos, A Kozma, E Adam, S Fekete & T Masszi

  3. Department of Hematology, Kaposi Mor Hospital, Kaposvar, Hungary

    M Egyed

  4. 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary

    J Varkonyi

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  1. H Andrikovics
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Correspondence to H Andrikovics.

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Andrikovics, H., Nahajevszky, S., Koszarska, M. et al. JAK2 46/1 haplotype analysis in myeloproliferative neoplasms and acute myeloid leukemia. Leukemia 24, 1809–1813 (2010). https://doi.org/10.1038/leu.2010.172

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