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Cited by 1,756Myeloproliferative Neoplasms: Diagnosis and TreatmentAcute Myeloid Leukemia ResearchPlatelet Disorders and Treatments

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Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2

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Nangalia, J., Massie, C.E., Baxter, E.J., Nice, F.L., Gundem, G., Wedge, D.C., Avezov, E., Li, J., Kollmann, K., Kent, D.G., Aziz, A., Godfrey, A.L., Hinton, J., Martincorena, I., Van Loo, P., Jones, A.V., Guglielmelli, P., Tarpey, P., Harding, H.P., Fitzpatrick, J.D., Goudie, C.T., Ortmann, C.A., Loughran, S.J., Raine, K., Jones, D.R., Butler, A.P., Teague, J.W., O'Meara, S., McLaren, S., Bianchi, M., Silber, Y., Dimitropoulou, D., Bloxham, D., Mudie, L., Maddison, M., Robinson, B., Keohane, C., Maclean, C., Hill, K., Orchard, K., Tauro, S., Du, M.-Q., Greaves, M., Bowen, D., Huntly, B.J.P., Harrison, C.N., Cross, N.C.P., Ron, D., Vannucchi, A.M., Papaemmanuil, E., Campbell, P.J., Green, A.R.·2013·New England Journal of Medicine
DOI 10.1056/nejmoa1312542PMC PMC3966280
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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.).

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  1. Chao MP, 2010, Sci Transl Med, 2, 63ra94

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Authors
Nangalia, J., Massie, C. E., Baxter, E. J., Nice, F. L., Gundem, G., Wedge, D. C., Avezov, E., Li, J., Kollmann, K., Kent, D. G., Aziz, A., Godfrey, A. L., Hinton, J., Martincorena, I., Van Loo, P., Jones, A. V., Guglielmelli, P., Tarpey, P., Harding, H. P., Fitzpatrick, J. D., Goudie, C. T., Ortmann, C. A., Loughran, S. J., Raine, K., Jones, D. R., Butler, A. P., Teague, J. W., O'Meara, S., McLaren, S., Bianchi, M., Silber, Y., Dimitropoulou, D., Bloxham, D., Mudie, L., Maddison, M., Robinson, B., Keohane, C., Maclean, C., Hill, K., Orchard, K., Tauro, S., Du, M.-Q., Greaves, M., Bowen, D., Huntly, B. J. P., Harrison, C. N., Cross, N. C. P., Ron, D., Vannucchi, A. M., Papaemmanuil, E., Campbell, P. J., & Green, A. R.
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2013-12-19
Volume
369
Issue
25
Pages
2391-2405
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1312542
PMC
PMC3966280
OpenAlex
W2138709799
Cited by
1,756
References
40
Citations by year
2026: 64 · 2025: 59 · 2024: 72 · 2023: 90 · 2022: 112 · 2021: 133 · 2020: 125 · 2019: 124 · 2018: 130 · 2017: 181 · 2016: 208 · 2015: 239 · 2014: 208 · 2013: 7
FWCI
108.50
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • University of Salford Institutional Repository (University of Salford) (submittedVersion, cc-by)
  • Discovery Research Portal (University of Dundee) (submittedVersion)
  • ePrints Soton (University of Southampton) (submittedVersion)
  • Florence Research (University of Florence) (submittedVersion)
  • Lirias (KU Leuven) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
Funders
  • Leukemia and Lymphoma Society
  • Leukemia and Lymphoma Research
  • University of Salford Manchester
  • Wellcome Trust (079249, 100140, 093867, 084812)
  • University Hospital Southampton NHS Foundation Trust
  • Cancer Research UK (12526, 12765, 15488)
  • National Institute for Health and Care Research (NF-SI-0512-10079)
  • Kay Kendall Leukaemia Fund
  • University of Southampton
  • KU Leuven
  • Università degli Studi di Firenze
  • Associazione Italiana per la Ricerca sul Cancro
  • Vlaamse regering
  • Canadian Institutes of Health Research
  • Medical Research Council
  • Cambridge Institute for Medical Research, University of Cambridge
  • NIHR Cambridge Biomedical Research Centre
  • Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze
Topics
  • Health Sciences › Medicine › Hematology › Myeloproliferative Neoplasms: Diagnosis and Treatment
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
Keywords
calreticulin, CALR mutation, myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, myelofibrosis, myelodysplastic syndrome, endoplasmic reticulum chaperone, clonal evolution, hematopoietic stem and progenitor cells, somatic mutations
MeSH terms
Amino Acid Sequence, Bone Marrow Diseases, Exons, Humans, Leukemia, Myeloid, Molecular Sequence Data, Mutation, Myelodysplastic Syndromes, Neoplasms, Thrombocythemia, Essential, Polymerase Chain Reaction, Sequence Analysis, DNA, Calreticulin, Janus Kinase 2, Primary Myelofibrosis

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