Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2
Open accessAbstract
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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Many of the most commonly seen mutations in CHIP are also recurrent drivers of AML, myelodysplastic syndrome (MDS), myeloproliferative neoplasms, and certain lymphomas.
“But many of the most commonly seen mutations in CHIP are also recurrent drivers of AML 64, myelodysplastic syndrome (MDS) 65–67, myeloproliferative neoplasms 68, and certain lymphomas 69,70.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [68]
CALR mutations frequently occur in Ph-negative MPNs, including ET, PMF, and PV.
“Calreticulin gene (CALR) mutations frequently occur in Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), primary myelofibrosis (PMF), and polycythemia vera (PV) [188–190].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [188]
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“But many of the most commonly seen mutations in CHIP are also recurrent drivers of AML (65), myelodysplastic syndrome (MDS) (66–68), myeloproliferative neoplasms (69), and certain lymphomas (70, 71).”
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Self-citation
- 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
- Nangalia, J.
- Massie, C.E.
- Baxter, E.J.
- Nice, F.L.
- Gundem, G.
- Wedge, D.C.
- Avezov, E.
- Kollmann, K.
- Kent, D.G.
- Godfrey, A.L.
- Hinton, J.
- Martincorena, I.
- Jones, A.V.
- Guglielmelli, P.
- Tarpey, P.
- Harding, H.P.
- Fitzpatrick, J.D.
- Loughran, S.J.
- Raine, K.
- Jones, D.R.
- Teague, J.W.
- McLaren, S.
- Hill, K.
- Orchard, K.
- 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.
- 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
- 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 · 2012: 3
- FWCI
- 108.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- 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 › Genetics › 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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