Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2
| Autor: | Mark Maddison, Heather P. Harding, Ming-Qing Du, Athar Aziz, David Bloxham, Kate Hill, Brian J. P. Huntly, Paola Guglielmelli, Charles E. Massie, David G. Kent, Bruce W. S. Robinson, Kim Orchard, Edward Avezov, Gunes Gundem, Nicholas C.P. Cross, Jonathon Hinton, Jyoti Nangalia, P Van Loo, David Ron, L. Mudie, Sarah O’Meara, E J Baxter, Stephen J. Loughran, Anthony R. Green, Christina A. Ortmann, Claire N. Harrison, Clodagh Keohane, David R. Jones, Karoline Kollmann, Anna L. Godfrey, David C. Wedge, D. Dimitropoulou, Inigo Martincorena, M. Bianchi, Alessandro M. Vannucchi, Mel Greaves, Juan Li, Cathy MacLean, Elli Papaemmanuil, Peter J. Campbell, Amy V. Jones, P. S. Tarpey, Keiran Raine, David G. Bowen, Francesca L. Nice, Yvonne Silber, Adam Butler, Jon W. Teague, Sudhir Tauro, J.D. Fitzpatrick, Stuart McLaren, C.T. Goudie |
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| Rok vydání: | 2013 |
| Předmět: |
0303 health sciences
Pathology medicine.medical_specialty Janus kinase 2 Essential thrombocythemia DCN MP - Plasticity and memory health_and_wellbeing General Medicine Biology medicine.disease 3. Good health 03 medical and health sciences 0302 clinical medicine Polycythemia vera 030220 oncology & carcinogenesis hemic and lymphatic diseases medicine Cancer research biology.protein CALR Exon 9 Mutation Myelofibrosis Calreticulin Myeloproliferative neoplasm Exome sequencing 030304 developmental biology |
| Zdroj: | The New England Journal of Medicine, 369, 25, pp. 2391-405 The New England Journal of Medicine, 369, 2391-405 |
| ISSN: | 0028-4793 |
| Popis: | Item does not contain fulltext 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.). |
| Databáze: | OpenAIRE |
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