期刊
LEUKEMIA
卷 30, 期 2, 页码 431-438出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2015.277
关键词
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资金
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- Fondo per gli investimenti della ricerca di base (FIRB) [RBAP11CZLK]
- Ministero dell'Istruzione, deli'Universita e della Ricerca (MIUR, PRIN)
- Italian Ministry of Health [GR-2010-2312855]
- AIRC [MFAG-2014-15672]
- Fondazione Cariplo [2010-0807]
- AIRC Special Program 'Molecular Clinical Oncology 5 per mille' (AIRC Gruppo Italiano Malattie Mieloproliferative (AGIMM)) [1005]
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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