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Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2

Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2
Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2
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.).
2391-2405
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Nice, Francesca L.
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Gundem, Gunes
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Cross, Nicholas C. P.
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Ron, David
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Vannucchi, Alessandro M.
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Papaemmanuil, Elli
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Campbell, Peter J.
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Green, Anthony R.
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Nangalia, Jyoti, Massie, Charles E., Baxter, E. Joanna, Nice, Francesca L., Gundem, Gunes, Wedge, David C., Avezov, Edward, Li, Juan, Kollmann, Karoline, Kent, David G., Aziz, Athar, Godfrey, Anna L., Hinton, Jonathan, Martincorena, Inigo, Van Loo, Peter, Jones, Amy V., Guglielmelli, Paola, Tarpey, Patrick, Harding, Heather P., Fitzpatrick, John D., Goudie, Calum T., Ortmann, Christina A., Loughran, Stephen J., Raine, Keiran, Jones, David R., Butler, Adam P., Teague, Jon W., O'Meara, Sarah, McLaren, Stuart, Bianchi, Michele, Silber, Yvonne, Dimitropoulou, Danai, Bloxham, David, Mudie, Laura, Maddison, Mark, Robinson, Ben, Keohane, Clodagh, Maclean, Cathy, Hill, Kate, Orchard, Kim, Tauro, Sudhir, Du, Ming-Qing, Greaves, Mel, Bowen, David, Huntly, Brian J. P., Harrison, Claire N., Cross, Nicholas C. P., Ron, David, Vannucchi, Alessandro M., Papaemmanuil, Elli, Campbell, Peter J. and Green, Anthony R. (2013) Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. New England Journal of Medicine, 369 (25), 2391-2405. (doi:10.1056/NEJMoa1312542). (PMID:24325359)

Record type: Article

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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More information

e-pub ahead of print date: 10 December 2013
Published date: 19 December 2013
Organisations: Cancer Sciences, Human Development & Health

Identifiers

Local EPrints ID: 360547
URI: http://eprints.soton.ac.uk/id/eprint/360547
PURE UUID: a52dc17f-b5e7-4910-bb3d-92775d810e3e
ORCID for Kim Orchard: ORCID iD orcid.org/0000-0003-2276-3925
ORCID for Nicholas C. P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

Catalogue record

Date deposited: 17 Dec 2013 11:02
Last modified: 23 Jul 2022 01:50

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Contributors

Author: Jyoti Nangalia
Author: Charles E. Massie
Author: E. Joanna Baxter
Author: Francesca L. Nice
Author: Gunes Gundem
Author: David C. Wedge
Author: Edward Avezov
Author: Juan Li
Author: Karoline Kollmann
Author: David G. Kent
Author: Athar Aziz
Author: Anna L. Godfrey
Author: Jonathan Hinton
Author: Inigo Martincorena
Author: Peter Van Loo
Author: Amy V. Jones
Author: Paola Guglielmelli
Author: Patrick Tarpey
Author: Heather P. Harding
Author: John D. Fitzpatrick
Author: Calum T. Goudie
Author: Christina A. Ortmann
Author: Stephen J. Loughran
Author: Keiran Raine
Author: David R. Jones
Author: Adam P. Butler
Author: Jon W. Teague
Author: Sarah O'Meara
Author: Stuart McLaren
Author: Michele Bianchi
Author: Yvonne Silber
Author: Danai Dimitropoulou
Author: David Bloxham
Author: Laura Mudie
Author: Mark Maddison
Author: Ben Robinson
Author: Clodagh Keohane
Author: Cathy Maclean
Author: Kate Hill
Author: Kim Orchard ORCID iD
Author: Sudhir Tauro
Author: Ming-Qing Du
Author: Mel Greaves
Author: David Bowen
Author: Brian J. P. Huntly
Author: Claire N. Harrison
Author: David Ron
Author: Alessandro M. Vannucchi
Author: Elli Papaemmanuil
Author: Peter J. Campbell
Author: Anthony R. Green

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