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.

  • Letter to the Editor
  • Published:

Report on two novel nucleotide exchanges in the JAK2 pseudokinase domain: D620E and E627E

Leukemia volume 20, pages 2195–2197 (2006)Cite this article

The V617F point mutation of the JAK2 gene (located in chromosome 9p24) shows a high frequency in diverse BCR-ABL-negative chronic myeloproliferative disorders. A thymidine>guanine substitution at position 1849 leads to a valine to phenylalanine exchange at amino acid 617, which is localized in exon 12. The highest frequency of point mutations of the JAK2 gene is found in polycythemia vera (80–95% of all cases), which is followed by essential thrombocytosis and idiopathic osteomyelofibrosis (40–55% of all cases). The mutation is further known to occur at low frequency in the so-called unclassifiable MPS (according to the WHO classification), in chronic myelomonocytic leukemia, in myelodysplastic syndrome and in acute myeloid leukemia (AML).1, 2, 3, 4, 5 The cytoplasmic nonreceptor Janus kinases regulate tyrosine phosphorylation of several essential signaling pathways for cell proliferation and apoptosis, for example, the JAK/STAT pathway. The V617F mutation induces hypersensitivity to cytokines or even independence from their influence in mutated cell lines and is conceived as gain-of-function mutation.1, 3, 6 It is situated in a highly conserved region of the JH2 pseudokinase domain of the JAK2 nonreceptor tyrosine kinase. The pseudokinase domain is involved in autoinhibition of the JAK2 tyrosine kinase activity by interaction of the amino acid 618 and surrounding residues with the activation loop of the JH1 kinase domain.1, 6, 7

All known reported point mutations of the JAK2 kinase in hematologic disorders represent the identical t1849g point mutation. The only exception is represented by a novel K607N mutation in a case of AML that had recently been reported by Lee et al.5 The NCBI single nucleotide polymorphism (SNP) database contains 435 SNPs of the JAK2 kinase (http://www-bimas.cit.nih.gov/cgi-bin/cards/carddisp.pl?gene=JAK2&search=JAK2&snp=435#snp). We here report on two novel single nucleotide exchanges located in the JAK2 pseudokinase domain.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144–1148.

    Article  CAS  Google Scholar 

  2. Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005; 106: 2162–2168.

    Article  CAS  Google Scholar 

  3. 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.

    Article  CAS  Google Scholar 

  4. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7: 387–397.

    Article  CAS  Google Scholar 

  5. Lee JW, Kim YG, Soung YH, Han KJ, Kim SY, Rhim HS et al. The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene 2006; 25: 1434–1436.

    Article  CAS  Google Scholar 

  6. Saharinen P, Takaluoma K, Silvennoinen O . Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol Cell Biol 2000; 20: 3387–3395.

    Article  CAS  Google Scholar 

  7. Lindauer K, Loerting T, Liedl KR, Kroemer RT . Prediction of the structure of human Janus kinase 2 (JAK2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation. Protein Eng 2001; 14: 27–37.

    Article  CAS  Google Scholar 

  8. Jaffe ES, Harris NL, Stein H, Vardiman JW . World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2001.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. MLL, Munich Leukemia Laboratory, Munich, Germany

    S Schnittger, W Kern, T Haferlach & C Schoch

  2. Department of Clinical Chemistry, University Hospital of Munich, Grosshadern, Munich, Germany

    U Bacher

  3. Vinzentius Krankenhaus, Landau, Germany

    M Schröder

Authors
  1. S Schnittger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. U Bacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W Kern
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Schröder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Haferlach
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Schoch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Schnittger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schnittger, S., Bacher, U., Kern, W. et al. Report on two novel nucleotide exchanges in the JAK2 pseudokinase domain: D620E and E627E. Leukemia 20, 2195–2197 (2006). https://doi.org/10.1038/sj.leu.2404325

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404325

This article is cited by

Search

Advanced search

Quick links