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Leukemia. 2016 Feb;30(2):431-8. doi: 10.1038/leu.2015.277. Epub 2015 Oct 9.

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

Author information

1
Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.
2
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
3
Biotechnology Research Laboratories, Fondazione IRCCS Policlinico, San Matteo, Pavia, Italy.
4
Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, Italy.
5
Anatomic Pathology Section, Fondazione IRCCS Policlinico, San Matteo, Pavia, Italy.
6
Center for the Study of Myelofibrosis, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
7
Department of Biomedical Engineering, Tufts University, Medford, MA, USA.

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.

PMID:
26449662
PMCID:
PMC4740452
DOI:
10.1038/leu.2015.277
[Indexed for MEDLINE]
Free PMC Article

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