1. INSERM U362, Institut Gustave Roussy, Paris XI University, PR1, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France
2. Laboratoire d'Hématologie, CHU Brest, 29609 Brest Cedex, France
3. Laboratoire d'Hématologie, Hôtel Dieu, AP-HP, 75181 Paris Cedex 04, France
4. Ludwig Institute for Cancer Research and Christian de Duve Institute of Cellular Pathology & MEXP Unit, Université Catholique de Louvain, Brussels B-1200, Belgium
5. INSERM E0210, Hôpital Necker, 75743 Paris Cedex 15, France
6. Laboratoire d'Hématologie, Institut Gustave Roussy, 94805 Villejuif Cedex, France
7. Polyclinique d'Hématologie, Hôpital Saint Louis, AP-HP, 75475 Paris Cedex 10, France
8. These authors contributed equally to this work

Correspondence to: William Vainchenker^1,7 Correspondence and requests for materials should be addressed to W.V. (Email: verpre@igr.fr).

Abstract

Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines^{1, 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 cytokines^{4, 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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