Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms

• Published in: The New England journal of medicine Vol. 369; no. 25; pp. 2379 - 2390
• Main Authors: Klampfl, Thorsten, Gisslinger, Heinz, Harutyunyan, Ashot S, Nivarthi, Harini, Rumi, Elisa, Milosevic, Jelena D, Them, Nicole C.C, Berg, Tiina, Gisslinger, Bettina, Pietra, Daniela, Chen, Doris, Vladimer, Gregory I, Bagienski, Klaudia, Milanesi, Chiara, Casetti, Ilaria Carola, Sant'Antonio, Emanuela, Ferretti, Virginia, Elena, Chiara, Schischlik, Fiorella, Cleary, Ciara, Six, Melanie, Schalling, Martin, Schönegger, Andreas, Bock, Christoph, Malcovati, Luca, Pascutto, Cristiana, Superti-Furga, Giulio, Cazzola, Mario, Kralovics, Robert
• Format: Journal Article
• Language: English
• Published: Waltham, MA Massachusetts Medical Society 19.12.2013
• Subjects: Biological and medical sciences; Blood; Bone Marrow Diseases - genetics; Calreticulin; Calreticulin - genetics; Exons; General aspects; Genes; Humans; Janus kinase; Janus kinase 2; Janus Kinase 2 - genetics; Leukemia, Myeloid - genetics; Medical sciences; Medical treatment; Mutation; Myelofibrosis; Neoplasia; Polycythemia; Polycythemia vera; Polymerase Chain Reaction; Primary Myelofibrosis - genetics; Primary Myelofibrosis - mortality; Proportional Hazards Models; Receptors, Thrombopoietin - genetics; Sequence Analysis, DNA; Stat5 protein; Thrombocythemia, Essential - complications; Thrombocythemia, Essential - genetics; Thrombocythemia, Essential - mortality; Thrombopoietin; Thrombosis; Thrombosis - etiology; Transcription; United States > US; Philadelphia Pennsylvania; Medicine; Tumor; Mutation
• ISSN: 0028-4793; 1533-4406; 1533-4406
• DOI: 10.1056/NEJMoa1311347

The authors identified calreticulin mutations in the majority of patients with essential thrombocythemia and myelofibrosis who did not have JAK2 mutations. The mutation alters calreticulin protein, and cells expressing the mutant protein are more responsive to growth factors. Philadelphia chromosome–negative myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. 1 A unique gain-of-function mutation in the Janus kinase 2 gene ( JAK2 ) is found in about three quarters of patients in whom these disease entities have been diagnosed. 2 , 3 The valine-to-phenylalanine (V617F) alteration constitutively activates JAK2, resulting in increased phosphorylation of its substrates and leading to increased cytokine responsiveness of myeloid cells. The JAK2 V617F mutation is present in approximately 95% of patients with polycythemia vera and in 50 to 60% of those with essential thrombocythemia or primary myelofibrosis. 4 In addition, somatic mutations of JAK2 exon 12 . . .