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.

A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms

Abstract

Genome-wide association studies have identified a number of new disease susceptibility loci that represent haplotypes defined by numerous SNPs. SNPs within a disease-associated haplotype are thought to influence either the expression of genes or the sequence of the proteins they encode. In a series of investigations of the JAK2 gene in myeloproliferative neoplasms, we uncovered a new property of haplotypes that can explain their disease association. We observed a nonrandom distribution of the somatic JAK2V617F oncogenic mutation between two parental alleles of the JAK2 gene. We identified a haplotype that preferentially acquires JAK2V617F and confers susceptibility to myeloproliferative neoplasms. One interpretation of our results is that a certain combination of SNPs may render haplotypes differentially susceptible to somatic mutagenesis. Thus, disease susceptibility loci may harbor somatic mutations that have a role in disease pathogenesis.

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: Cytogenetic analysis of hematopoietic progenitor clones in a subject with primary myelofibrosis.
Figure 2: Detection of multiple acquisitions of the JAK2V617F mutation in exon 14 of the JAK2 gene in MPN.
Figure 3: Association analysis results for eight SNPs from the JAK2 genomic region.
Figure 4: Determination of the JAK2 gene haplotypes that carry JAK2V617F in 17 subjects with uniparental disomy of chromosome 9p (9pUPD).

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. Scott, L.M. et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N. Engl. J. Med. 356, 459–468 (2007).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  7. Pardanani, A.D. et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 108, 3472–3476 (2006).

    Article  CAS  Google Scholar 

  8. Plo, I. et al. JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders. Blood 112, 1402–1412 (2008).

    Article  CAS  Google Scholar 

  9. Kralovics, R. et al. Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood 108, 1377–1380 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Levi, S. et al. Multiple K-ras codon 12 mutations in cholangiocarcinomas demonstrated with a sensitive polymerase chain reaction technique. Cancer Res. 51, 3497–3502 (1991).

    CAS  PubMed  Google Scholar 

  12. Sozzi, G. et al. Genetic evidence for an independent origin of multiple preneoplastic and neoplastic lung lesions. Cancer Res. 55, 135–140 (1995).

    CAS  PubMed  Google Scholar 

  13. Moskaluk, C.A., Hruban, R.H. & Kern, S.E. p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res. 57, 2140–2143 (1997).

    CAS  PubMed  Google Scholar 

  14. Laghi, L. et al. Lack of mutation at codon 531 of SRC in advanced colorectal cancers from Italian patients. Br. J. Cancer 84, 196–198 (2001).

    Article  CAS  Google Scholar 

  15. Agaimy, A. et al. Multiple sporadic gastrointestinal stromal tumors (GISTs) of the proximal stomach are caused by different somatic KIT mutations suggesting a field effect. Am. J. Surg. Pathol. 32, 1553–1559 (2008).

    Article  Google Scholar 

  16. Li, S. et al. Clonal heterogeneity in polycythemia vera patients with JAK2 exon12 and JAK2–V617F mutations. Blood 111, 3863–3866 (2008).

    Article  CAS  Google Scholar 

  17. 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 

  18. Laken, S.J. et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat. Genet. 17, 79–83 (1997).

    Article  CAS  Google Scholar 

  19. Mechanic, L.E. et al. Common genetic variation in TP53 is associated with lung cancer risk and prognosis in African Americans and somatic mutations in lung tumors. Cancer Epidemiol. Biomarkers Prev. 16, 214–222 (2007).

    Article  CAS  Google Scholar 

  20. Lin, M. et al. dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics 20, 1233–1240 (2004).

    Article  CAS  Google Scholar 

  21. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  22. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The study was supported by funding from the Austrian Academy of Sciences, Austrian Science Fund (FWF, P20033-B11) and the Initiative for Cancer Research of the Medical University of Vienna. We thank C. Ay and N. Bachhofner for help with sample collection and T. Burkard for advice on statistical analysis. We thank H. Pickersgill for help with the manuscript.

Author information

Authors and Affiliations

Authors

Contributions

R.K. designed the study and drafted the paper with assistance of D.O. and A.H.; D.O., T.B. and R.J. performed the experiments; D.O. and A.H. performed statistical analyses; T.B., B.G., H.G. and I.P. coordinated and performed the case and control sample collection and clinical management of cases.

Corresponding author

Correspondence to Robert Kralovics.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1 and 2 (PDF 272 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Olcaydu, D., Harutyunyan, A., Jäger, R. et al. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet 41, 450–454 (2009). https://doi.org/10.1038/ng.341

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.341

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