JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms.
Amy V. Jones,Andrew Chase,Richard T. Silver,David Oscier,Katerina Zoi,Y. Lynn Wang,Holger Cario,Heike L. Pahl,Andrew Collins,Andreas Reiter,Francis H. Grand,Nicholas C.P. Cross +11 more
TLDR
It is reported here that JAK2V617F-associated disease is strongly associated with a specific constitutional Jak2 haplotype, designated 46/1, in all three disease entities compared to healthy controls and provides a model whereby a constitutional genetic factor is associated with an increased risk of acquiring a specific somatic mutation.Abstract:
Chronic myeloproliferative neoplasms (MPNs) are a group of related conditions characterized by the overproduction of cells from one or more myeloid lineages. More than 95% of cases of polycythemia vera, and roughly half of essential thrombocythemia and primary myelofibrosis acquire a unique somatic 1849G>T JAK2 mutation (encoding V617F) that is believed to be a critical driver of excess proliferation. We report here that JAK2(V617F)-associated disease is strongly associated with a specific constitutional JAK2 haplotype, designated 46/1, in all three disease entities compared to healthy controls (polycythemia vera, n = 192, P = 2.9 x 10(-16); essential thrombocythemia, n = 78, P = 8.2 x 10(-9) and myelofibrosis, n = 41, P = 8.0 x 10(-5)). Furthermore, JAK2(V617F) specifically arises on the 46/1 allele in most cases. The 46/1 JAK2 haplotype thus predisposes to the development of JAK2(V617F)-associated MPNs (OR = 3.7; 95% CI = 3.1-4.3) and provides a model whereby a constitutional genetic factor is associated with an increased risk of acquiring a specific somatic mutation.read more
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Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders
Thomas Ernst,Andrew Chase,Andrew Chase,Joannah Score,Joannah Score,Claire Hidalgo-Curtis,Claire Hidalgo-Curtis,Catherine Bryant,Catherine Bryant,Amy V. Jones,Amy V. Jones,Katherine Waghorn,Katherine Waghorn,Katerina Zoi,Fiona M. Ross,Fiona M. Ross,Andreas Reiter,Andreas Hochhaus,Hans G. Drexler,Andrew S Duncombe,Francisco Cervantes,David Oscier,Jacqueline Boultwood,Francis H. Grand,Francis H. Grand,Nicholas C.P. Cross,Nicholas C.P. Cross +26 more
TL;DR: In this article, the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy was described, and the mutations resulted in premature chain termination or direct abrogation of histone methyltransferase activity.
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JAKs and STATs in Immunity, Immunodeficiency, and Cancer
TL;DR: A large number of cytokines signal through the JAK–STAT pathway, and normal function of this pathway may lead to a variety of diseases.
Journal ArticleDOI
Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms
Pontus Lundberg,Axel Karow,Ronny Nienhold,Renate Looser,Hui Hao-Shen,Ina Nissen,Sabine Girsberger,Thomas Lehmann,Jakob Passweg,Martin Stern,Christian Beisel,Robert Kralovics,Robert Kralovics,Radek C. Skoda +13 more
TL;DR: Surprisingly, the number of mutations between early and late patient samples did not significantly change, and during a total follow-up of 133 patient years, only 2 new mutations appeared, suggesting that the mutation rate in MPN is rather low.
Journal ArticleDOI
Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2 , MPL , TET2 , ASXL1 , CBL , IDH and IKZF1
TL;DR: The functional consequences of MPN-associated mutations including unregulated JAK-STAT signaling, epigenetic modulation of transcription and abnormal accumulation of oncoproteins are not clear as to whether and how these abnormalities contribute to disease initiation, clonal evolution or blastic transformation.
Journal ArticleDOI
JAK/STAT signaling in hematological malignancies
William Vainchenker,William Vainchenker,William Vainchenker,Stefan N. Constantinescu,Stefan N. Constantinescu +4 more
TL;DR: The nature and respective contribution of mutations dysregulating the JAK/STAT pathway in hematological malignancies are discussed and examples in which such mutations drive the disease, contribute to the phenotype, or provide a survival and proliferative advantage are presented.
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TL;DR: This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
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A Comparison of Bayesian Methods for Haplotype Reconstruction from Population Genotype Data
Matthew Stephens,Peter Donnelly +1 more
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Journal ArticleDOI
A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders
Robert Kralovics,Francesco Passamonti,Andreas Buser,Soon Siong Teo,Ralph Tiedt,Jakob Passweg,André Tichelli,Mario Cazzola,Radek C. Skoda +8 more
TL;DR: Genetic evidence and in vitro functional studies indicate that V617F gives hematopoietic precursors proliferative and survival advantages and a high proportion of patients with myeloproliferative disorders carry a dominant gain-of-function mutation of JAK2.
Journal ArticleDOI
Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.
E. Joanna Baxter,Linda M. Scott,Peter J. Campbell,Clare L. East,Nasios Fourouclas,Soheila Swanton,George S. Vassiliou,Anthony J. Bench,Elaine M. Boyd,Natasha Curtin,Michael A. Scott,Wendy N. Erber,Anthony R. Green,Anthony R. Green +13 more
TL;DR: A single acquired mutation of JAK2 was noted in more than half of patients with a myeloproliferative disorder and its presence in all erythropoietin-independent erythroid colonies demonstrates a link with growth factor hypersensitivity, a key biological feature of these disorders.
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
TL;DR: 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.
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