Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2

By J. Nangalia, C. Massie, E. Baxter, Francesca L. Nice, G. Gundem, David C. Wedge, E. Avezov, Juan Li, K. Kollmann, D. Kent and 42 more. New England Journal of Medicine, 2013

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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.)

Subfields: Genetics, Pathology and Forensic Medicine, Rheumatology

View Paper: https://www.semanticscholar.org/paper/cc3fa7681f1bec9797191889d027a76efda969b2

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Citations in the corpus

Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. (2014, neutral): “Neutrophils (10(9)/L) average (range) 9 (2-36) 6 (3-16) 8 (3-21)”
Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer (2023, background): “Whole-exome sequencing identified CALR mutations in ~70% to 80% of JAK2-negative ETs and primary myelofibrosis.(232,233) In vivo research demonstrated that CALR mutation alone was strong enough to initiate an MPN phenotype and increased JAK-STAT signaling activity.”
Clonal hematopoiesis in human aging and disease (2019, background): “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).”
The role of mutations in epigenetic regulators in myeloid malignancies (2012, background): “However, in one study, overexpression of mutant CALR in BaF3 cells, a mouse pro-B cell line, led to cytokine-independent growth and increased levels of phosphorylated STAT5 (108).”