Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms

Abstract

Chronic myeloproliferative neoplasms (MPNs) are a group of related conditions characterized by the overproduction of cells from one or more myeloid lineages. More than 95% of cases of polycythemia vera, and roughly half of essential thrombocythemia and primary myelofibrosis acquire a unique somatic 1849G>T JAK2 mutation (encoding V617F) that is believed to be a critical driver of excess proliferation1,2,3,4. We report here that JAK2V617F-associated disease is strongly associated with a specific constitutional JAK2 haplotype, designated 46/1, in all three disease entities compared to healthy controls (polycythemia vera, n = 192, P = 2.9 × 10−16; essential thrombocythemia, n = 78, P = 8.2 × 10−9 and myelofibrosis, n = 41, P = 8.0 × 10−5). Furthermore, JAK2V617F specifically arises on the 46/1 allele in most cases. The 46/1 JAK2 haplotype thus predisposes to the development of JAK2V617F-associated MPNs (OR = 3.7; 95% CI = 3.1–4.3) and provides a model whereby a constitutional genetic factor is associated with an increased risk of acquiring a specific somatic mutation.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Allele distortions due to aUPD enable direct reading of JAK2 haplotypes.
Figure 2: SNPs, haplotypes and LD around JAK2.
Figure 3: Familial polycythemia vera pedigree.
Figure 4: Association between JAK2 haplotype and numbers of hemopoietic colonies.

References

  1. James, C. et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434, 1144–1148 (2005).

    Article  CAS  Google Scholar 

  2. Kralovics, R. et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779–1790 (2005).

    Article  CAS  Google Scholar 

  3. Levine, R.L. et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7, 387–397 (2005).

    Article  CAS  Google Scholar 

  4. Baxter, E.J. et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365, 1054–1061 (2005).

    Article  CAS  Google Scholar 

  5. Kralovics, R., Guan, Y. & Prchal, J.T. Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp. Hematol. 30, 229–236 (2002).

    Article  CAS  Google Scholar 

  6. Jones, A.V. et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 106, 2162–2168 (2005).

    Article  CAS  Google Scholar 

  7. Pikman, Y. et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 3, e270 (2006).

    Article  Google Scholar 

  8. Kralovics, R. Genetic complexity of myeloproliferative neoplasms. Leukemia 22, 1841–1848 (2008).

    Article  CAS  Google Scholar 

  9. Rumi, E. et al. Disease anticipation in familial myeloproliferative neoplasms. Blood 112, 2587–2588 (2008).

    Article  CAS  Google Scholar 

  10. Landgren, O. et al. Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24, 577 first-degree relatives of 11, 039 patients with myeloproliferative neoplasms in Sweden. Blood 112, 2199–2204 (2008).

    Article  CAS  Google Scholar 

  11. Pardanani, A., Fridley, B.L., Lasho, T.L., Gilliland, D.G. & Tefferi, A. Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders. Blood 111, 2785–2789 (2008).

    Article  CAS  Google Scholar 

  12. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  13. Stephens, M. & Donnelly, P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am. J. Hum. Genet. 73, 1162–1169 (2003).

    Article  CAS  Google Scholar 

  14. Cario, H., Goerttler, P.S., Steimle, C., Levine, R.L. & Pahl, H.L. The JAK2V617F mutation is acquired secondary to the predisposing alteration in familial polycythaemia vera. Br. J. Haematol. 130, 800–801 (2005).

    Article  CAS  Google Scholar 

  15. Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).

    Article  CAS  Google Scholar 

  16. Sandberg, E.M., Wallace, T.A., Godeny, M.D., VonDerLinden, D. & Sayeski, P.P. Jak2 tyrosine kinase: a true jak of all trades? Cell Biochem. Biophys. 41, 207–232 (2004).

    Article  Google Scholar 

  17. Khoury, M.J., Beaty, T.H. & Cohen, B.H. Fundamentals of Genetic Epidemiology (Oxford University Press, New York, 1993).

  18. Easton, D.F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).

    Article  CAS  Google Scholar 

  19. Eeles, R.A. et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat. Genet. 40, 316–321 (2008).

    Article  CAS  Google Scholar 

  20. Di Bernardo, M.C. et al. A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nat. Genet. 40, 1204–1210 (2008).

    Article  CAS  Google Scholar 

  21. Jones, A.V. et al. Minimal molecular response in polycythemia vera patients treated with imatinib or interferon alpha. Blood 107, 3339–3341 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by Leukaemia Research (UK) Specialist Programme Grant 0280 and makes use (in part) of data generated by the WTCCC. A full list of the investigators who contributed to the generation of the WTCCC data are available from www.wtccc.org.uk, funding for which was provided by the Wellcome Trust under award 076113. We are grateful to P. Strike (Salisbury Research and Development Support Unit) for statistical advice. A.R. was supported by the Deutsche José Carreras Leukämie-Stiftung e.V. - DJCLS R06/02, Germany.

Author information

Authors and Affiliations

Authors

Contributions

The study was designed by A.V.J., A. Chase., F.G. and N.C.P.C. A.V.J. performed the laboratory analysis. R.T.S., D.O., K.Z., Y.L.W., H.L.P., H.C. and A.R. provided clinical samples and associated information. A.V.J., A. Chase, A. Collins and N.C.P.C. analyzed the data. N.C.P.C. wrote the first draft of the manuscript and all authors contributed to and approved the final version.

Corresponding author

Correspondence to Nicholas C P Cross.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1 and Supplementary Table 1 (PDF 45 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jones, A., Chase, A., Silver, R. et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet 41, 446–449 (2009). https://doi.org/10.1038/ng.334

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.334

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing