Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders
Abstract
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 cel…
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The JAK2 V617F gain-of-function mutation is present in about 95% of PV, 50-60% of ET, and about 50% of PMF patients and is associated with increased risk of mortality and splenomegaly.
“the JAK2 gain-of-function mutation (V617F) has been suggested to play a prominent role in MPNs (Baxter et al., 2005; Levine et al., 2005), being present in in ∼95% of PV, 50% to 60% of ET, and ∼50% of all PMF patients and associated with increased risk of mortality and splenomegaly”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Baxter et al., 2005
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- Authors
- Baxter, E. J., Scott, L. M., Campbell, P. J., East, C., Fourouclas, N., Swanton, S., Vassiliou, G. S., Bench, A. J., Boyd, E. M., Curtin, N., Scott, M. A., Erber, W. N., & Green, A. R.
- Affiliations
- University of Cambridge (GB)
- Addenbrooke's Hospital (GB)
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2005-03
- Volume
- 365
- Issue
- 9464
- Pages
- 1054-1061
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2144664431
- Cited by
- 3,548
- References
- 0
- Citations by year
- 2026: 66 · 2025: 77 · 2024: 98 · 2023: 126 · 2022: 130 · 2021: 141 · 2020: 145 · 2019: 135 · 2018: 126 · 2017: 158 · 2016: 176 · 2015: 204 · 2014: 193 · 2013: 201 · 2012: 210
- FWCI
- 109.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (088340)
- Topics
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- JAK2, myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, tyrosine kinase, acquired mutations, mitotic recombination, molecular pathogenesis
- MeSH terms
- Chromosomes, Human, Pair 9, Colony-Forming Units Assay, Granulocytes, Hematopoietic Stem Cells, Humans, Myeloproliferative Disorders, Polycythemia Vera, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Thrombocythemia, Essential, Signal Transduction, Polymerase Chain Reaction, Point Mutation, In Situ Hybridization, Fluorescence, Loss of Heterozygosity, Janus Kinase 2, Primary Myelofibrosis
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