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|Ref Type||Journal Article|
|Authors||Pietra D, Rumi E, Ferretti VV, Buduo CA, Milanesi C, Cavalloni C, Sant'Antonio E, Abbonante V, Moccia F, Casetti IC, Bellini M, Renna MC, Roncoroni E, Fugazza E, Astori C, Boveri E, Rosti V, Barosi G, Balduini A, Cazzola M|
|Title||Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms.|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
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|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
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|CALR mutant||bone marrow cancer||not applicable||N/A||Clinical Study||Diagnostic||CALR mutations are used in the diagnosis of myeloproliferative neoplasms, especially of essential thrombocythemia and primary myelofibrosis (PMID: 26697989, PMID: 26449662, PMID: 26071474, PMID: 25873496).||26697989 25873496 26449662 26071474|