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:

AML1–ETO meets JAK2: clinical evidence for the two hit model of leukemogenesis from a myeloproliferative syndrome progressing to acute myeloid leukemia

Leukemia volume 21, pages 2199–2201 (2007)Cite this article

The two hit model of acute myeloid leukemia (AML) was proposed by Gilliland,1 based on experimental data in mouse transplantation models. While expression of an activated tyrosine kinase like FLT3 induced myeloproliferation, an additional genetic hit, for example a mutated transcription factor blocking myeloid differentiation, was necessary to cause leukemia.

JAK2 is a cytoplasmatic tyrosine-kinase critical for signal transduction of type I cytokine receptors, for example EPO-R.2 The somatic point mutation JAK2V617F is frequently found in patients with myeloproliferative disorders,3, 4, 5, 6 but seems to be rare in other myeloid malignancies such as myelodysplastic syndromes7 or AML.8 Our own unpublished data and recent publications show the coexistence of JAK2V617 and AML1–ETO in AML at a frequency of 5–6%8, 9, 10 hypothesizing that both mutations cooperate in leukemogenesis.

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
Figure 2
Figure 3

References

  1. Gilliland DG . Hematologic malignancies. Curr Opin Hematol 2001; 8: 189–191.

    Article  CAS  Google Scholar 

  2. Lu X, Levine R, Tong W, Wernig G, Pikman Y, Zarnegar S et al. Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation. Proc Natl Acad Sci USA 2005; 102: 18962–18967.

    Article  CAS  Google Scholar 

  3. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Cancer Genome Project et al. Acquired mutation of the tyrosine-kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 366: 122.

    Article  Google Scholar 

  4. Levine RL, Wadleigh M, Colls 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. 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 polycythemia vera. Nature 2005; 434: 1144–1148.

    Article  CAS  Google Scholar 

  6. 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 

  7. Steensma DP, Dewald GW, Lasho TL, Powell HL, McClure RF, Levine RL et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both ‘atypical’ myeloproliferative disorders and myelodysplastic syndromes. Blood 2005; 106: 1207–1209.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Döhner K, Du J, Corbacioglu A, Scholl C, Schlenk RF, Döhner H . JAK2V617F mutations as cooperative genetic lesions in t(8;21)-positive acute myeloid leukemia. Haematologica 2006; 91: 1571–1572.

    Google Scholar 

  10. Schnittger S, Bacher U, Kern W, Haferlach C, Haferlach W . JAK2 seems to be a typical cooperating mutation in therapy-related t(8;21)/AML1-ETO-positive AML. Leukemia 2007; 21: 183–184.

    Article  CAS  Google Scholar 

  11. Dunlop EA, Percy MJ, Boland MP, Maxwell AP, Lappin TR . Induction of signalling in non-erythroid cells by pharmacological levels of Erythropoietin. Neurodegener Dis 2006; 3: 94–100.

    Article  CAS  Google Scholar 

  12. Schessl C, Rawat VP, Cusan M, Desphande A, Kohl TM, Rosten PM et al. The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukaemia in mice. J Clin Invest 2005; 115: 2159–2168.

    Article  CAS  Google Scholar 

  13. Schwaller J, Frantsve J, Aster J, Williams IR, Tomasson MH, Ross TS et al. Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes. EMBO J 1998; 17: 5321–5333.

    Article  CAS  Google Scholar 

  14. Najean Y, Rain JD . Treatment of polycythemia vera - use of P-32 alone or in combination with maintenance therapy using hydroxyurea in 461 patients greater than 65 years of age. Blood 1997; 89: 2319.

    CAS  Google Scholar 

  15. Landaw SA . Acute leukaemia in polycythemia vera. In: Polycythemia Vera and the Myeloproliferative diseases. WB Saunders: Philadelphia, 1995, pp 154.

    Google Scholar 

  16. Calabretta B, Perrotti D . The biology of CML blast crisis. Blood 2004; 103: 4010–4022.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine III, Laboratory for Leukemia Diagnostics, University Hospital Grosshadern, Ludwig-Maximilians University Marchioninistr, München, Germany

    F Schneider, S K Bohlander, S Schneider, C Papadaki, P Kakadyia, A Dufour, M Unterhalt, M Feuring-Buske, C Buske, J Braess, W Hiddemann & K Spiekermann

  2. Clinical Cooperative Group, Acute Leukemia GSF Research Center for Environment and Health, Marchioninistr., München, Germany

    S K Bohlander, P Kakadyia, S Vempati, M Feuring-Buske, C Buske, J Braess, W Hiddemann & K Spiekermann

  3. Department of Medicine V, Hospital Nürnberg North, Nürnberg, Germany

    H Wandt

Authors
  1. F Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S K Bohlander
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Papadaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P Kakadyia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Dufour
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Vempati
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Unterhalt
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Feuring-Buske
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C Buske
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J Braess
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. H Wandt
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. W Hiddemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. K Spiekermann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Spiekermann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schneider, F., Bohlander, S., Schneider, S. et al. AML1–ETO meets JAK2: clinical evidence for the two hit model of leukemogenesis from a myeloproliferative syndrome progressing to acute myeloid leukemia. Leukemia 21, 2199–2201 (2007). https://doi.org/10.1038/sj.leu.2404830

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404830

This article is cited by

Search

Advanced search

Quick links