Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis
Open accessAbstract
Polycythemia vera (PV), essential thrombocythemia (ET), and myeloid metaplasia with myelofibrosis (MMM) are clonal disorders arising from hematopoietic progenitors. An internet-based protocol was used to collect clinical information and biological specimens from patients with these diseases. High-throughput DNA resequencing identified a recurrent somatic missense mutation JAK2V617F in granulocyte DNA samples of 121 of 164 PV patients, of which 41 had homozygous and 80 had heterozygous mutations. Molecular and cytogenetic analyses demonstrated that homozygous mutations were due to duplication of the mutant allele. JAK2V617F was also identified in granulocyte DNA samples from 37 of 115 ET and 16 of 46 MMM patients, but was not observed in 269 normal individuals. In vitro analysis demonstrated that JAK2V617F is a constitutively active tyrosine kinase.
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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 Levine et al., 2005
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- Authors
- Levine, R. L., Wadleigh, M., Cools, J., Ebert, B. L., Wernig, G., Huntly, B. J. P., Boggon, T. J., Wlodarska, I., Clark, J. J., Moore, S., Adelsperger, J., Koo, S., Lee, J. C., Gabriel, S., Mercher, T., D’Andrea, A., Fröhling, S., Döhner, K., Marynen, P., Vandenberghe, P., Mesa, R. A., Tefferi, A., Griffin, J. D., Eck, M. J., Sellers, W. R., Meyerson, M., Golub, T. R., Lee, S. J., & Gilliland, D. G.
- Affiliations
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- KU Leuven (BE)
- Broad Institute (US)
- University Hospital Ulm (DE)
- Mayo Clinic (US)
- Corresponding author
- Lee, Stephanie J.
- Gilliland, D. Gary
- ORCID
- Levine, Ross L.
- Wadleigh, Martha
- Cools, Jan
- Ebert, Benjamin L.
- Wernig, Gerlinde
- Huntly, Brian J.P.
- Boggon, Titus J.
- Clark, Jennifer J.
- Gabriel, Stacey
- Mercher, Thomas
- D’Andrea, Alan
- Fröhling, Stefan
- Döhner, Konstanze
- Vandenberghe, Peter
- Mesa, Ruben A.
- Tefferi, Ayalew
- Griffin, James D.
- Eck, Michael J.
- Sellers, William R.
- Meyerson, Matthew
- Golub, Todd R.
- Lee, Stephanie J.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2005-04
- Volume
- 7
- Issue
- 4
- Pages
- 387-397
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2057360098
- Cited by
- 2,993
- References
- 4
- Citations by year
- 2026: 52 · 2025: 54 · 2024: 78 · 2023: 104 · 2022: 99 · 2021: 133 · 2020: 113 · 2019: 103 · 2018: 101 · 2017: 129 · 2016: 149 · 2015: 157 · 2014: 175 · 2013: 183 · 2012: 180
- FWCI
- 97.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (#CA66996, T32CA009172, P01CA066996)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 50654, P01DK050654)
- Topics
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Keywords
- JAK2 V617F mutation, JAK2, polycythemia vera, essential thrombocythemia, somatic missense mutations, tyrosine kinase activation, homozygous mutation, clonal hematopoietic disorders, constitutive kinase activity
- MeSH terms
- Adult, Aged, Aged, 80 and over, Enzyme Activation, Female, Genotype, Granulocytes, Heterozygote, Homozygote, Humans, Male, Middle Aged, Mitosis, Models, Molecular, Mouth Mucosa, Phosphorylation, Polycythemia Vera, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Recombination, Genetic, Thrombocythemia, Essential, Transfection, Mutation, Missense, Cell Line, Tumor, Janus Kinase 2, Primary Myelofibrosis
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