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Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms
Open accessAbstract
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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“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 [189]
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Metadata
- 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
- 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
- bronze
- doi.org
- 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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