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Analyses of TET2 mutations in post-myeloproliferative neoplasm acute myeloid leukemias

Leukemia volume 24, pages 201–203 (2010)Cite this article

Classic myeloproliferative neoplasms (MPN) include essential thrombocythemia, polycythemia vera and primitive myelofibrosis.1 These diseases are characterized by an over production of myeloid cells and may transform into acute myeloblastic leukemia (AML). An acquired point mutation that leads to the expression of a constitutively active form of the Janus kinase 2 (JAK2) tyrosine kinase, JAK2V617F, is observed in almost all polycythemia vera cases, and in 50–60% of essential thrombocythemia and primitive myelofibrosis. In experimental models, JAK2V617F recapitulates most of the features of MPN, establishing its essential role in the clinical phenotype of the diseases. It is, however, unclear how a single mutation gives rise to three related but distinct disorders. Moreover, when AML develops in a patient with a JAK2V617F-positive myeloproliferative neoplasm, the fully transformed clone is often JAK2V617F negative.2 These and other observations suggested that, in some patients, another unknown mutation has preceded the JAK2V617F mutation in the development of MPN.3 Recent publications have reported acquired mutations of the TET2 gene in various hematopoietic malignancies.4 The most frequent type of variation affecting TET2 interrupts the open reading frame of the gene. In MPN, TET2 mutations were observed in both JAK2V617F-positive and -negative patients and in both JAK2V617F-positive and -negative clones in individual patients.5

We were particularly interested in patient 4, for whom chronic phase cDNA was available. Molecular analyses of this patient have already been reported as patient BO-04.7 She suffered from essential thrombocythemia and the JAK2V617F mutation was present only in a fraction of neutrophils. At the transformation phase, the blasts were devoid of the JAK2V617F mutation,7 but a C → T variation was observed resulting in the creation of a stop codon (p.Gln803X, Figures 1a and b). The identified TET2 mutation was searched in the cDNA obtained from chronic phase peripheral blood cells. As shown in Figure 1b, the TET2 mutation was already present in the chronic phase sample, and the ratio between wild-type and mutated nucleotide was roughly similar between the two phases. These data indicated that, although JAK2V617F had been observed in a minority of myeloid cells, TET2 mutations were present in the majority of blood cells. Unfortunately, no material from neutrophils at the chronic phase was available, precluding any experimental confirmation that TET2 and JAK2 mutations had been present in the same cells. Nevertheless, our data strongly suggest that in patient 4, TET2-mutated AML derived from TET2-mutated JAK2 wild-type cells was present during the chronic phase.

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References

  1. Tefferi A, Vardiman JW . Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008; 22: 14–22.

    Article  CAS  Google Scholar 

  2. Kilpivaara O, Levine RL . JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science. Leukemia 2008; 22: 1813–1817.

    Article  CAS  Google Scholar 

  3. Kralovics R . Genetic complexity of myeloproliferative neoplasms. Leukemia 2008; 22: 1841–1848.

    Article  CAS  Google Scholar 

  4. Mullighan CG . TET2 mutations in myelodysplasia and myeloid malignancies. Nat Genet 2009; 41: 766–767.

    Article  CAS  Google Scholar 

  5. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360: 2289–2301.

    Article  Google Scholar 

  6. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009; 324: 930–935.

    Article  CAS  Google Scholar 

  7. Theocharides A, Boissinot M, Girodon F, Garand R, Teo SS, Lippert E et al. Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood 2007; 110: 375–379.

    Article  CAS  Google Scholar 

  8. Shigesada K, van de Sluis B, Liu PP . Mechanism of leukemogenesis by the inv(16) chimeric gene CBFB/PEBP2B-MHY11. Oncogene 2004; 23: 4297–4307.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by INSERM, INCa, the Fondation de France and the Ligue Nationale Contre le Cancer. We thank William Vainchenker for critical reading of the manuscript.

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Authors and Affiliations

  1. INSERM E210, Hôpital Necker-Enfants Malades,

    L Couronné & O A Bernard

  2. Université René Descartes, Paris, France

    L Couronné & O A Bernard

  3. Laboratoire de Cytogénétique, CHU, Bordeaux, France

    E Lippert

  4. Laboratoire de Génétique Médicale, CHU, Lille, France

    J Andrieux

  5. Service d'Hématologie Biologique, CHU Cochin, Paris, France

    O Kosmider

  6. Université René Descartes, Paris, France

    O Kosmider

  7. Laboratoire de Cytogénétique, Hôpital Necker-Enfants Malades, Paris, France

    I Radford-Weiss

  8. Génétique Oncologique, Centre H Becquerel, Rouen, France

    D Penther

  9. Génétique des Hémopathies, CHU, Toulouse, France

    N Dastugue

  10. Laboratoire de Cytogénétique, CHU, Dijon, France

    F Mugneret

  11. Laboratoire de Cytogénétique, CHU La Timone, Marseille, France

    M Lafage

  12. Laboratoire de Cytogénétique, CHU, Limoges, France

    N Gachard

  13. Laboratoire de Cytogénétique, CHU, St-Etienne, France

    N Nadal

  14. Service d'Hématologie Biologique, Hôpital Pitié-Salpêtrière,

    F Nguyen-Khac

  15. INSERM, U872, Paris, France

    F Nguyen-Khac

  16. Université Pierre et Marie Curie-Paris 6,

    F Nguyen-Khac

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Correspondence to F Nguyen-Khac.

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Couronné, L., Lippert, E., Andrieux, J. et al. Analyses of TET2 mutations in post-myeloproliferative neoplasm acute myeloid leukemias. Leukemia 24, 201–203 (2010). https://doi.org/10.1038/leu.2009.169

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