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

D. Pietra, E. Rumi, V. V. Ferretti, C. A. Di Buduo, C. Milanesi, C. Cavalloni, E. Sant'Antonio, V. Abbonante, F. Moccia, I. C. Casetti, M. Bellini, M. C. Renna, E. Roncoroni, E. Fugazza, C. Astori, E. Boveri, V. Rosti, G. Barosi, A. Balduini, M. Cazzola

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)431-438
Number of pages8
JournalLeukemia
Volume30
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

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ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Pietra, D., Rumi, E., Ferretti, V. V., Di Buduo, C. A., 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. (2016). Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia, 30(2), 431-438. https://doi.org/10.1038/leu.2015.277