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

• Published in: Leukemia 2016-02, Vol.30 (2), p.431-438
• Main Authors: Pietra, D, Rumi, E, Ferretti, V V, Buduo, C A Di, Milanesi, C, Cavalloni, C, Sant'Antonio, E, Abbonante, V, Moccia, F, Casetti, I C, Bellini, M, Renna, M C, Roncoroni, E, Fugazza, E, Astori, C, Boveri, E, Rosti, V, Barosi, G, Balduini, A, Cazzola, M
• Format: Article
• Language: English
• Subjects: 631/208/737; 631/67/68; 631/80/86/1999; 692/308/575; 692/699/1541; 692/699/1541/1990/2331; Adolescent; Adult; Aged; Aged, 80 and over; Calcium - metabolism; Calreticulin - genetics; Cancer Research; Cells, Cultured; Critical Care Medicine; Development and progression; Exons; Female; Gene mutations; Genetic aspects; Health aspects; Hematology; Humans; Intensive; Internal Medicine; Isoelectric Point; Lectins; Male; Medicine; Medicine & Public Health; Megakaryocytes - metabolism; Middle Aged; Mutation; Myeloproliferative disorders; Oncology; Original; original-article; Primary Myelofibrosis - genetics; Primary Myelofibrosis - metabolism; Thrombocythemia, Essential - genetics; Thrombocythemia, Essential - metabolism
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2015.277

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.