Bioinformatic analyses of CALR mutations in myeloproliferative neoplasms support a role in signaling

Eder-Azanza, Laura; Navarro, Diego; Aranaz, Paula; Novo, Francisco J.; Cross, Nicholas C. P.; Vizmanos, José Luis

doi:10.1038/leu.2014.190

Cited by 20 publications

(12 citation statements)

References 15 publications

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“… 12 A bioinformatic analysis of CALR mutations has indeed shown that only +1 frameshift mutations (that is, those observed in MPN patients) exhibit a positively charged C-terminus. 35 Interestingly, type 1 CALR mutation and more generally exon 9 deletions create mutant proteins with more altered calcium binding activity. 35 , 36 Since cytoplasmic Ca 2+ levels regulate human Mk 22 and platelet function, 37 we reasoned that different CALR mutants might differentially contribute to the pathogenesis of MPN.…”

Section: Discussionmentioning

confidence: 99%

Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms

et al. 2015

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A quarter of patients with essential thrombocythemia or primary myelofibrosis carry a driver mutation of CALR, the calreticulin gene. A 52-bp deletion (type 1) and a 5-bp insertion (type 2 mutation) are the most frequent variants. These indels might differentially impair the calcium binding activity of mutant calreticulin. We studied the relationship between mutation subtype and biological/clinical features of the disease. Thirty-two different types of CALR variants were identified in 311 patients. Based on their predicted effect on calreticulin C-terminal, mutations were classified as: (i) type 1-like (65%); (ii) type 2-like (32%); and (iii) other types (3%). Corresponding CALR mutants had significantly different estimated isoelectric points. Patients with type 1 mutation, but not those with type 2, showed abnormal cytosolic calcium signals in cultured megakaryocytes. Type 1-like mutations were mainly associated with a myelofibrosis phenotype and a significantly higher risk of myelofibrotic transformation in essential thrombocythemia. Type 2-like CALR mutations were preferentially associated with an essential thrombocythemia phenotype, low risk of thrombosis despite very-high platelet counts and indolent clinical course. Thus, mutation subtype contributes to determining clinical phenotype and outcomes in CALR-mutant myeloproliferative neoplasms. CALR variants that markedly impair the calcium binding activity of mutant calreticulin are mainly associated with a myelofibrosis phenotype.

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Section: Discussionmentioning

confidence: 99%

Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms

et al. 2015

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“…6 In the current study, we used statistical models 7 to calculate helix propensity for 31 unique amino acid sequences that were altered by CALR mutations, and we used the results to subclassify non-type 1/2 CALR mutations into "type 1-like" and "type 2-like" variants.…”

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confidence: 99%

The prognostic advantage of calreticulin mutations in myelofibrosis might be confined to type 1 or type 1-like CALR variants

Tefferi

Lasho

Tischer

et al. 2014

Blood

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115

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“…Th e diff erences are likely to be due to diff erent pathogenetic mechanisms of individual CALR mutations [24]. Recently, investigators also reported relevant structural and functional diff erences between proteins encoded by various CALR gene variations [26]. However, relatively low numbers of MF cases with type 2 CALR mutations in studies published so far prevent deeper understanding of how the CALR mutation type aff ects the OS.…”

Section: Discussionmentioning

confidence: 99%

Effect of CALR and JAK2 mutations on the clinical and hematological phenotypes of the disease in patients with myelofibrosis – long-term experience from a single center

Palová¹,

Szotkowski²,

Hluší³

et al. 2018

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Primary myelofibrosis (PMF) is a chronic clonal myeloid disorder. Together with essential thrombocythemia (ET) and polycythemia vera (PV), it belongs to a group of Philadelphia chromosome-negative myeloproliferative neoplasms. An integral part of laboratory tests carried out in this disease group is detecting the presence of mutations in the Janus kinase 2 gene at position 617 (JAK2 V617F) and in the gene encoding for the receptor for thrombopoietin (myeloproliferative leukemia virus oncogene, MPL) found in approximately 60% of PMF patients. The discovery of mutations affecting exon 9 of the calreticulin (CALR) gene was of great benefit to the diagnosis of the diseases in JAK2 V617F and MPL unmutated cases. This is a study of the effect of a mutation in the CALR gene on the clinical course in patients with primary, post-ET and post-PV myelofibrosis. Analysis of 66 patients (54.5% JAK2 V617F; 34.8% CALR; 6.1% MPL; 3.0% triple negative; 1.5% coincidence of CALR and JAK2 V617F) confirmed a different phenotype of the disease in CALR-mutated patients as compared with CALR-unmutated individuals. Those with CALR mutation were significantly younger and had borderline higher platelet counts, less pronounced splenomegaly and less frequent B symptoms at diagnosis. The study suggests that the driver mutation types define variations in the biological basis, clinical manifestations and course of the disease. The presence of CALR mutation has been shown to be an independent prognostic favorable factor. Careful risk stratification of these patients is of great importance to adequate therapeutic decision-making and aids in selecting high-risk patients eligible for allogeneic hematopoietic stem cell transplantation which continues to be the only treatment modality for myelofibrosis having curative potential.

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Bioinformatic analyses of CALR mutations in myeloproliferative neoplasms support a role in signaling

Cited by 20 publications

References 15 publications

Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms

Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms

The prognostic advantage of calreticulin mutations in myelofibrosis might be confined to type 1 or type 1-like CALR variants

Effect of CALR and JAK2 mutations on the clinical and hematological phenotypes of the disease in patients with myelofibrosis – long-term experience from a single center

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