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Cited by 2,003Myeloproliferative Neoplasms: Diagnosis and TreatmentAcute Myeloid Leukemia ResearchPlatelet Disorders and Treatments

The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.

Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms

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Klampfl, Thorsten, Gisslinger, Heinz, Harutyunyan, Ashot S., Nivarthi, Harini, Rumi, Elisa, Milosevic, Jelena D., Them, Nicole C.C., Berg, Tiina, Gisslinger, Bettina, Pietra, Daniela, Chen, Doris, Vladimer, Gregory I., Bagienski, Klaudia, Milanesi, Chiara, Casetti, Ilaria Carola, Sant'Antonio, Emanuela, Ferretti, Virginia, Elena, Chiara, Schischlik, Fiorella, Cleary, Ciara, Six, Melanie, Schalling, Martin, Schönegger, Andreas, Bock, Christoph, Malcovati, Luca, Pascutto, Cristiana, Superti-Furga, Giulio, Cazzola, Mario, Kralovics, Robert·2013·New England Journal of Medicine
DOI 10.1056/nejmoa1311347
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Abstract

BACKGROUND: Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an additional 5 to 10% have activating mutations in the thrombopoietin receptor gene (MPL). So far, no specific molecular marker has been identified in the remaining 30 to 45% of patients. METHODS: We performed whole-exome sequencing to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Resequencing of CALR, encoding calreticulin, was then performed in cohorts of patients with myeloid neoplasms. RESULTS: Somatic insertions or deletions in exon 9 of CALR were detected in all patients who underwent whole-exome sequencing. Resequencing in 1107 samples from patients with myeloproliferative neoplasms showed that CALR mutations were absent in polycythemia vera. In essential thrombocythemia and primary myelofibrosis, CALR mutations and JAK2 and MPL mutations were mutually exclusive. Among patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 or MPL, CALR mutations were detected in 67% of those with essential thrombocythemia and 88% of those with primary myelofibrosis. A total of 36 types of insertions or deletions were identified that all cause a frameshift to the same alternative reading frame and generate a novel C-terminal peptide in the mutant calreticulin. Overexpression of the most frequent CALR deletion caused cytokine-independent growth in vitro owing to the activation of signal transducer and activator of transcription 5 (STAT5) by means of an unknown mechanism. Patients with mutated CALR had a lower risk of thrombosis and longer overall survival than patients with mutated JAK2. CONCLUSIONS: Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR. The clinical course in these patients was more indolent than that in patients with the JAK2 V617F mutation. (Funded by the MPN Research Foundation and Associazione Italiana per la Ricerca sul Cancro.).

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Authors
Klampfl, T., Gisslinger, H., Harutyunyan, A. S., Nivarthi, H., Rumi, E., Milosevic, J. D., Them, N. C. C., Berg, T., Gisslinger, B., Pietra, D., Chen, D., Vladimer, G. I., Bagienski, K., Milanesi, C., Casetti, I. C., Sant'Antonio, E., Ferretti, V., Elena, C., Schischlik, F., Cleary, C., Six, M., Schalling, M., Schönegger, A., Bock, C., Malcovati, L., Pascutto, C., Superti-Furga, G., Cazzola, M., & Kralovics, R.
Affiliations
  • Austrian Academy of Sciences (AT)
  • Medical University of Vienna (AT)
  • Policlinico San Matteo Fondazione (IT)
  • University of Pavia (IT)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2013-12-19
Volume
369
Issue
25
Pages
2379-2390
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1311347
OpenAlex
W2157694607
Cited by
2,003
References
32
Citations by year
2026: 80 · 2025: 63 · 2024: 81 · 2023: 117 · 2022: 122 · 2021: 173 · 2020: 144 · 2019: 146 · 2018: 153 · 2017: 200 · 2016: 247 · 2015: 243 · 2014: 222 · 2013: 7
FWCI
118.00
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • INFM-OAR (INFN Catania) (submittedVersion, other-oa)
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, essential thrombocythemia, primary myelofibrosis, JAK2 V617F mutation, MPL mutation, somatic mutations, exon 9 deletion, frameshift mutation, STAT5 activation, thrombosis risk, overall survival
MeSH terms
Bone Marrow Diseases, Exons, Humans, Leukemia, Myeloid, Mutation, Thrombocythemia, Essential, Thrombosis, Proportional Hazards Models, Polymerase Chain Reaction, Sequence Analysis, DNA, Calreticulin, Janus Kinase 2, Receptors, Thrombopoietin, Primary Myelofibrosis

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