Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms
| Autor: | Chiara Milanesi, Chiara Cavalloni, Emanuela Sant'Antonio, Mario Cazzola, Maria C. Renna, Emanuela Boveri, Ilaria Carola Casetti, Vittorio Rosti, Elisa Roncoroni, Daniela Pietra, Elisa Rumi, Elena Fugazza, Cesare Astori, Vittorio Abbonante, C. A. Di Buduo, Francesco Moccia, Marta Bellini, Alessandra Balduini, G Barosi, Virginia Valeria Ferretti |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Adult Male Cancer Research medicine.medical_specialty Adolescent Mutant Biology medicine.disease_cause 03 medical and health sciences Exon 0302 clinical medicine Internal medicine medicine Humans Isoelectric Point Myelofibrosis Cells Cultured Aged Genetics Aged 80 and over Mutation Hematology Essential thrombocythemia Exons Middle Aged medicine.disease Phenotype 030104 developmental biology Oncology Primary Myelofibrosis 030220 oncology & carcinogenesis Cancer research biology.protein Original Article Calcium Female Calreticulin Megakaryocytes Thrombocythemia Essential |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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