title: Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms.
abstract: 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.
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Pietra
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.|Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Rumi
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.
authors.forename: V V
authors.initials: VV
authors.lastname: Ferretti
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.|Biotechnology Research Laboratories, Fondazione IRCCS Policlinico, San Matteo, Pavia, Italy.
authors.forename: C A
authors.initials: CA
authors.lastname: Di Buduo
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Milanesi
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Cavalloni
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Sant'Antonio
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.|Biotechnology Research Laboratories, Fondazione IRCCS Policlinico, San Matteo, Pavia, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Abbonante
authors.affiliation: Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Moccia
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: I C
authors.initials: IC
authors.lastname: Casetti
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bellini
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Renna
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Roncoroni
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Fugazza
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Astori
authors.affiliation: Anatomic Pathology Section, Fondazione IRCCS Policlinico, San Matteo, Pavia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Boveri
authors.affiliation: Biotechnology Research Laboratories, Fondazione IRCCS Policlinico, San Matteo, Pavia, Italy.|Center for the Study of Myelofibrosis, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Rosti
authors.affiliation: Biotechnology Research Laboratories, Fondazione IRCCS Policlinico, San Matteo, Pavia, Italy.|Center for the Study of Myelofibrosis, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Barosi
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.|Biotechnology Research Laboratories, Fondazione IRCCS Policlinico, San Matteo, Pavia, Italy.|Department of Biomedical Engineering, Tufts University, Medford, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Balduini
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.|Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cazzola
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002118:Calcium / Q000378:metabolism; D037282:Calreticulin / Q000235:genetics*; D002478:Cells, Cultured; D005091:Exons; D005260:Female; D006801:Humans; D007526:Isoelectric Point; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000378:metabolism; D013920:Thrombocythemia, Essential / Q000235:genetics* / Q000378:metabolism
chemical_list: D037282:Calreticulin; D002118:Calcium