title: 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 cytokines. 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 splenomegaly. Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines. 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.
authors.affiliation: INSERM U362, Institut Gustave Roussy, Paris XI University, PR1, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: James
authors.forename: Valérie
authors.initials: V
authors.lastname: Ugo
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Le Couédic
authors.forename: Judith
authors.initials: J
authors.lastname: Staerk
authors.forename: François
authors.initials: F
authors.lastname: Delhommeau
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacout
authors.forename: Loïc
authors.initials: L
authors.lastname: Garçon
authors.forename: Hana
authors.initials: H
authors.lastname: Raslova
authors.forename: Roland
authors.initials: R
authors.lastname: Berger
authors.forename: Annelise
authors.initials: A
authors.lastname: Bennaceur-Griscelli
authors.forename: Jean Luc
authors.initials: JL
authors.lastname: Villeval
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.forename: Nicole
authors.initials: N
authors.lastname: Casadevall
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
mesh_terms: D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology; D005091:Exons / Q000235:genetics; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D053614:Janus Kinase 2; D051379:Mice; D009154:Mutation / Q000235:genetics*; D011086:Polycythemia; D011087:Polycythemia Vera / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D004921:Erythropoietin; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2