Journal ArticleDOI
A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera
Chloé James,Valérie Ugo,Jean-Pierre Le Couedic,Judith Staerk,François Delhommeau,Catherine Lacout,Loïc Garçon,Hana Raslova,Roland Berger,Annelise Bennaceur-Griscelli,Jean-Luc Villeval,Stefan N. Constantinescu,Nicole Casadevall,William Vainchenker +13 more
TLDR
A clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model.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 splenomegaly(3). 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.read more
Citations
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Journal ArticleDOI
The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes
James W. Vardiman,Juergen Thiele,Daniel A. Arber,Richard D. Brunning,Michael J. Borowitz,Anna Porwit,Nancy L. Harris,Michelle M. Le Beau,Eva Hellström-Lindberg,Ayalew Tefferi,Clara D. Bloomfield +10 more
TL;DR: The classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.
Journal ArticleDOI
Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms
Thorsten Klampfl,Heinz Gisslinger,Ashot S. Harutyunyan,Harini Nivarthi,Elisa Rumi,Jelena D. Milosevic,Nicole C.C. Them,Tiina Berg,Bettina Gisslinger,Daniela Pietra,Doris Chen,Gregory I. Vladimer,Klaudia Bagienski,Chiara Milanesi,Ilaria Carola Casetti,Emanuela Sant'Antonio,Virginia Valeria Ferretti,Chiara Elena,Fiorella Schischlik,Ciara Cleary,Melanie Six,Martin Schalling,Andreas Schönegger,Christoph Bock,Luca Malcovati,Cristiana Pascutto,Giulio Superti-Furga,Mario Cazzola,Robert Kralovics +28 more
TL;DR: Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR, and patients with mutated CALR had a lower risk ofThrombosis and longer overall survival than patients with mutations in J AK2.
Journal ArticleDOI
Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2
Jyoti Nangalia,Charles E. Massie,E J Baxter,Francesca L. Nice,Gunes Gundem,David C. Wedge,Edward Avezov,Juan Li,Karoline Kollmann,David G. Kent,Athar Aziz,Anna L. Godfrey,Jonathon Hinton,Inigo Martincorena,P Van Loo,Amy V. Jones,Paola Guglielmelli,P. S. Tarpey,Heather P. Harding,J.D. Fitzpatrick,C.T. Goudie,Christina A. Ortmann,Stephen J. Loughran,Keiran Raine,David R. Jones,Adam Butler,Jon W. Teague,Sarah O’Meara,Stuart McLaren,M. Bianchi,Yvonne Silber,D. Dimitropoulou,David Bloxham,L. Mudie,Mark Maddison,Bruce W. S. Robinson,Clodagh Keohane,Cathy MacLean,Kate Hill,Kim Orchard,Sudhir Tauro,Ming-Qing Du,Mel Greaves,David G. Bowen,Brian J. P. Huntly,Claire N. Harrison,Nicholas C.P. Cross,David Ron,Alessandro M. Vannucchi,Elli Papaemmanuil,Peter J. Campbell,Anthony R. Green +51 more
TL;DR: Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2, a finding consistent with its role as an initiating mutation in some patients.
Journal ArticleDOI
Targeting the IL-6/JAK/STAT3 signalling axis in cancer.
TL;DR: Treatments that target the IL-6/JAK/STAT3 pathway in patients with cancer are poised to provide therapeutic benefit by directly inhibiting tumour cell growth and by stimulating antitumour immunity.
Journal ArticleDOI
Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals
Mervin C. Yoder,Laura E. Mead,Daniel N. Prater,Theresa R. Krier,Karim N. Mroueh,Fang Li,Rachel Krasich,Constance J. Temm,Josef T. Prchal,David A. Ingram +9 more
TL;DR: It is established that CFU-ECs are not EPCs and the role of these cells in angiogenesis must be re-examined prior to further clinical trials, whereas ECFCs may serve as a potential therapy for vascular regeneration.
References
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Journal ArticleDOI
JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin
Bruce A. Witthuhn,Frederick W. Quelle,Olli Silvennoinen,Taolin Yi,Bo Tang,Osamu Miura,James N. Ihle +6 more
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Journal ArticleDOI
A TEL-JAK2 Fusion Protein with Constitutive Kinase Activity in Human Leukemia
Virginie Lacronique,Virginie Lacronique,Anthony Boureux,Anthony Boureux,Véronique Della Valle,Véronique Della Valle,Hélène Poirel,Hélène Poirel,Christine Tran Quang,Christine Tran Quang,M. Mauchauffe,M. Mauchauffe,Christian Berthou,Christian Berthou,Michel Lessard,Michel Lessard,Roland Berger,Roland Berger,Jacques Ghysdael,Jacques Ghysdael,Olivier A. Bernard,Olivier A. Bernard +21 more
TL;DR: TEL-induced oligomerization of TEL-JAK2 resulted in the constitutive activation of its tyrosine kinase activity and conferred cytokine-independent proliferation to the interleukin-3-dependent Ba/F3 hematopoietic cell line.
Journal ArticleDOI
Polycythemia vera: myths, mechanisms, and management.
TL;DR: Polycythemia vera is a clonal disorder arising in a multipotent hematopoietic progenitor cell that causes the accumulation of morphologically normal red cells, white cells, platelets, and their progenitors in the absence of a definable stimulus.
Journal ArticleDOI
Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor.
TL;DR: The cloning of the human IL-TIF cDNA is reported, which shares 79% amino acid identity with mouse IL- TIF and 25% identity withhuman IL-10, suggesting that this cytokine contributes to the inflammatory response in vivo.
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