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SomaticCALRMutations in myeloproliferative neoplasms with nonmutatedJAK2

Nangalia, J, Massie, CE, Baxter, EJ, Nice, FL, Gundem, G, Wedge, DC, Avezov, E, Li, J, Kollmann, K, Kent, DG and Aziz, A; et al. 2013, 'SomaticCALRMutations in myeloproliferative neoplasms with nonmutatedJAK2' , New England Journal of Medicine, 369 (25) , pp. 2391-2405.

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Abstract

BACKGROUND: Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge. METHODS: We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry. RESULTS: Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients. CONCLUSIONS: Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2. (Funded by the Kay Kendall Leukaemia Fund and others.).

Item Type: Article
Themes: Health and Wellbeing
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Refereed: Yes
ISSN: 0028-4793
Related URLs:
Funders: Kay Kandel Fund, LLR, CRUK
Depositing User: Dr Athar Aziz
Date Deposited: 25 Feb 2015 15:08
Last Modified: 25 Feb 2015 15:18
URI: http://usir.salford.ac.uk/id/eprint/33631

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