A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.
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.
James
Chloé
C
INSERM U362, Institut Gustave Roussy, Paris XI University, PR1, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France.
Ugo
Valérie
V
Le Couédic
Jean-Pierre
JP
Staerk
Judith
J
Delhommeau
François
F
Lacout
Catherine
C
Garçon
Loïc
L
Raslova
Hana
H
Berger
Roland
R
Bennaceur-Griscelli
Annelise
A
Villeval
Jean Luc
JL
Constantinescu
Stefan N
SN
Casadevall
Nicole
N
Vainchenker
William
W
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
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