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.).

DOI: 10.1056/NEJMoa1312542

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@article{Nangalia2013SomaticCM, title={Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.}, author={J Nangalia and C E Massie and E J Baxter and F L Nice and G Gundem and D C Wedge and E Avezov and J Li and K Kollmann and D G Kent and A Aziz and A L Godfrey and J Hinton and I Martincorena and P Van Loo and A V Jones and P Guglielmelli and P Tarpey and H P Harding and J D Fitzpatrick and C T Goudie and C A Ortmann and S J Loughran and K Raine and D R Jones and A P Butler and J W Teague and S O'Meara and S McLaren and M Bianchi and Y Silber and D Dimitropoulou and D Bloxham and L Mudie and M Maddison and B Robinson and C Keohane and C Maclean and K Hill and K Orchard and S Tauro and M-Q Du and M Greaves and D Bowen and B J P Huntly and C N Harrison and N C P Cross and D Ron and A M Vannucchi and E Papaemmanuil and P J Campbell and A R Green}, journal={The New England journal of medicine}, year={2013}, volume={369 25}, pages={2391-2405} }