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Cited by 3,470Myeloproliferative Neoplasms: Diagnosis and TreatmentPlatelet Disorders and TreatmentsAcute Myeloid Leukemia Research

A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders

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Kralovics, Robert, Passamonti, Francesco, Buser, Andreas S., Teo, Soon-Siong, Tiedt, Ralph, Passweg, Jakob R., Tichelli, Andre, Cazzola, Mario +1 more·2005·New England Journal of Medicine
DOI 10.1056/nejmoa051113
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Abstract

BACKGROUND: Polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are clonal myeloproliferative disorders arising from a multipotent progenitor. The loss of heterozygosity (LOH) on the short arm of chromosome 9 (9pLOH) in myeloproliferative disorders suggests that 9p harbors a mutation that contributes to the cause of clonal expansion of hematopoietic cells in these diseases. METHODS: We performed microsatellite mapping of the 9pLOH region and DNA sequencing in 244 patients with myeloproliferative disorders (128 with polycythemia vera, 93 with essential thrombocythemia, and 23 with idiopathic myelofibrosis). RESULTS: Microsatellite mapping identified a 9pLOH region that included the Janus kinase 2 (JAK2) gene. In patients with 9pLOH, JAK2 had a homozygous G-->T transversion, causing phenylalanine to be substituted for valine at position 617 of JAK2 (V617F). All 51 patients with 9pLOH had the V617F mutation. Of 193 patients without 9pLOH, 66 were heterozygous for V617F and 127 did not have the mutation. The frequency of V617F was 65 percent among patients with polycythemia vera (83 of 128), 57 percent among patients with idiopathic myelofibrosis (13 of 23), and 23 percent among patients with essential thrombocythemia (21 of 93). V617F is a somatic mutation present in hematopoietic cells. Mitotic recombination probably causes both 9pLOH and the transition from heterozygosity to homozygosity for V617F. Genetic evidence and in vitro functional studies indicate that V617F gives hematopoietic precursors proliferative and survival advantages. Patients with the V617F mutation had a significantly longer duration of disease and a higher rate of complications (fibrosis, hemorrhage, and thrombosis) and treatment with cytoreductive therapy than patients with wild-type JAK2. CONCLUSIONS: A high proportion of patients with myeloproliferative disorders carry a dominant gain-of-function mutation of JAK2.

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  • Ruxolitinib has been internationally approved for therapy of myelofibrosis and polycythemia vera, which are frequently caused by the V617F gain-of-function mutation within JAK2.

    “The JAK1/2 inhibitor Ruxolitinib/INCB018424 (Jakavi/Jakafi, Incyte Pharmaceuticals, Novartis; Lin et al., 2009; Quintas-Cardama et al., 2010) has been internationally approved for the therapy of myelofibrosis (Mesa et al., 2012; Verstovsek et al., 2012) and polycythemia vera (Vannucchi et al., 2015), which are frequently caused by the V617F gain-of-function mutation within JAK2 (Kralovics et al.,”

    From Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib (2017) · cites this paper as Kralovics et al., 2005

  • Activating mutations in JAK2 allow constitutive signaling through growth factor receptors, leading to clonal expansion by enhanced proliferation of cells that carry this mutation.

    “Activating mutations in JAK2 allow constitutive signaling though growth factor receptors, thus leading to clonal expansion by enhanced proliferation of cells that carry this mutation 45.”

    From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [45]

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Authors
Kralovics, R., Passamonti, F., Buser, A. S., Teo, S.-S., Tiedt, R., Passweg, J. R., Tichelli, A., Cazzola, M., & Skoda, R. C.
Affiliations
  • University of Pavia (IT)
  • University Hospital of Basel (CH)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2005-04-28
Volume
352
Issue
17
Pages
1779-1790
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa051113
OpenAlex
W1980568348
Cited by
3,470
References
0
Citations by year
2026: 67 · 2025: 74 · 2024: 98 · 2023: 122 · 2022: 143 · 2021: 140 · 2020: 137 · 2019: 136 · 2018: 124 · 2017: 157 · 2016: 170 · 2015: 184 · 2014: 196 · 2013: 193 · 2012: 210
FWCI
104.86
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • IrInSubria (University of Insubria) (submittedVersion)
Funders
  • National Science Foundation
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
  • Associazione Italiana per la Ricerca sul Cancro
  • Krebsliga Beider Basel
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
gain-of-function mutations, myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, primary myelofibrosis, loss of heterozygosity, chromosome 9p, mitotic recombination, somatic mutations, disease progression, cytoreductive therapy
MeSH terms
Adolescent, Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Chromosomes, Human, Pair 9, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Polycythemia Vera, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Thrombocytosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Case-Control Studies, Point Mutation, Microsatellite Repeats, Loss of Heterozygosity, Janus Kinase 2, Primary Myelofibrosis

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