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A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera

Abstract

Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines1,2. The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly3. Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines4,5. Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.

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Figure 1: Erythropoietin-independent growth in polycythaemia vera cells is dependent on JAK2.
Figure 2: An acquired activating mutation in the 12th exon of JAK2.
Figure 3: Mutated JAK2 induces constitutive signalling leading to growth factor independence.
Figure 4: Erythrocytosis induced in recipient mice after transplantation with bone marrow cells transduced with mutated JAK2.

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Acknowledgements

The authors are grateful to M.-H. Courtier, E. Leclerc and A. Tonon for technical assistance, P. Marynen and J. Cools for providing the human JAK2 cDNA, and J. Feunteun, F. Wendling and O. Bernard for scientific discussions. We thank I. Teyssandier and C. Marzac for their help in collecting polycythaemia vera samples, and J.-C. Brouet, S. Cheze, J.-J. Kiladjian, F. Lellouche, M. Leporrier, M. Macro, P. Morel, O. Reman, L. Roy, A.-L. Taksin, B. Varet and J.-P. Vilque for their help in collecting samples and clinical data. We are also grateful to the patients for their agreement in participating in this study. This work was supported by grants from La Ligue Nationale contre le Cancer (équipe labellisée 2003), la Fédération belge contre le cancer and the FNRS, Belgium. C.J. was supported by a fellowship from the Fondation pour la Recherche Médicale. J.S. was a recipient of a Marie Curie fellowship and of a Daimler-Benz PhD fellowship. S.N.C. is a Research Associate of the FNRS. W.V. is supported by an interface contract between INSERM and IGR.

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Correspondence to William Vainchenker.

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Supplementary information

Supplementary Method S1

5'-3' sequences of PCR and sequencing JAK2 primers. This shows all the primer sequences used for DNA amplification and sequencing. (DOC 49 kb)

Supplementary Method S2

Details of the technique of dual luciferase assays are given. (DOC 14 kb)

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James, C., Ugo, V., Le Couédic, JP. et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434, 1144–1148 (2005). https://doi.org/10.1038/nature03546

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