Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders

E. Joanna Baxter, Linda M. Scott, Peter J. Campbell, Clare East, Nasios Fourouclas, Soheila Swanton, George S. Vassiliou, Anthony J. Bench, Elaine M. Boyd, Natasha Curtin, Mike A. Scott, Wendy N. Erber, Tim Avis, Andy Barthorpe, Graham Bignell, Matthew Blow, Lisa Brackenbury, Gemma Buck, Sheila Clegg, Jody ClementsJennifer Cole, Helen Davies, Sarah Edkins, Kristian Gray, Matthew Gorton, Sarah O'Meara, Kelly Halliday, Rachel Harrison, Wendy Haynes, Katy Hills, Chris Hunter, David Jones, Vivienne Kosmidou, Ross Laman, Richard Lugg, Adrian Parker, Janet Perry, Robert Petty, Alexandra Small, Helen Solomon, Philip Stephens, Yvonne Stephens, Claire Stevens, Raffaella Smith, Patrick Tarpey, Calli Tofts, Jennifer Varian, Sofie West, Sara Widaa, Sally Bamford, Adam Butler, Elizabeth Dawson, Ed Dicks, Ken Edwards, Simon Forbes, Chris Greenman, Jonathan Hinton, Andy Menzies, Keiran Raine, Rebecca Shepherd, Jon Teague, Andrew Yates, Richard Wooster, Andy Futreal, Mike Stratton, Anthony R. Green

Research output: Contribution to journalArticlepeer-review

3079 Citations (Scopus)


Background: Human myeloproliferative disorders form a range of clonal haematological malignant diseases, the main members of which are polycythaemia vera, essential thrombocythaemia, and idiopathic myelofibrosis. The molecular pathogenesis of these disorders is unknown, but tyrosine kinases have been implicated in several related disorders. We investigated the role of the cytoplasmic tyrosine kinase JAK2 in patients with a myeloproliferative disorder. Methods: We obtained DNA samples from patients with polycythaemia vera, essential thrombocythaemia, or idiopathic myelofibrosis. The coding exons of JAK2 were bidirectionally sequenced from peripheral-blood granulocytes, T cells, or both. Allele-specific PCR, molecular cytogenetic studies, microsatellite PCR, Affymetrix single nucleotide polymorphism array analyses, and colony assays were undertaken on subgroups of patients. Findings: A single point mutation (Val617Phe) was identified in JAK2 in 71 (97%) of 73 patients with polycythaemia vera, 29 (57%) of 51 with essential thrombocythaemia, and eight (50%) of 16 with idiopathic myelofibrosis. The mutation is acquired, is present in a variable proportion of granulocytes, alters a highly conserved valine present in the negative regulatory JH2 domain, and is predicted to dysregulate kinase activity. It was heterozygous in most patients, homozygous in a subset as a result of mitotic recombination, and arose in a multipotent progenitor capable of giving rise to erythroid and myeloid cells. The mutation was present in all erythropoietin-independent erythroid colonies. Interpretation: A single acquired mutation of JAK2 was noted in more than half of patients with a myeloproliferative disorder. Its presence in all erythropoietin-independent erythroid colonies demonstrates a link with growth factor hypersensitivity, a key biological feature of these disorders. Relevance to practice: Identification of the Val617Phe JAK2 mutation lays the foundation for new approaches to the diagnosis, classification, and treatment of myeloproliferative disorders.

Original languageEnglish
Pages (from-to)1054-1061
Number of pages8
Issue number9464
Publication statusPublished - 19 Mar 2005
Externally publishedYes


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