title: Somatic mutations of calreticulin in myeloproliferative neoplasms.
abstract: BACKGROUND
  Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an additional 5 to 10% have activating mutations in the thrombopoietin receptor gene (MPL). So far, no specific molecular marker has been identified in the remaining 30 to 45% of patients.
  
  
  METHODS
  We performed whole-exome sequencing to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Resequencing of CALR, encoding calreticulin, was then performed in cohorts of patients with myeloid neoplasms.
  
  
  RESULTS
  Somatic insertions or deletions in exon 9 of CALR were detected in all patients who underwent whole-exome sequencing. Resequencing in 1107 samples from patients with myeloproliferative neoplasms showed that CALR mutations were absent in polycythemia vera. In essential thrombocythemia and primary myelofibrosis, CALR mutations and JAK2 and MPL mutations were mutually exclusive. Among patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 or MPL, CALR mutations were detected in 67% of those with essential thrombocythemia and 88% of those with primary myelofibrosis. A total of 36 types of insertions or deletions were identified that all cause a frameshift to the same alternative reading frame and generate a novel C-terminal peptide in the mutant calreticulin. Overexpression of the most frequent CALR deletion caused cytokine-independent growth in vitro owing to the activation of signal transducer and activator of transcription 5 (STAT5) by means of an unknown mechanism. Patients with mutated CALR had a lower risk of thrombosis and longer overall survival than patients with mutated JAK2.
  
  
  CONCLUSIONS
  Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR. The clinical course in these patients was more indolent than that in patients with the JAK2 V617F mutation. (Funded by the MPN Research Foundation and Associazione Italiana per la Ricerca sul Cancro.).
authors: From CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (T.K., A.S.H., H.N., J.D.M., N.C.C.T., T.B., D.C., G.I.V., K.B., F.S., C.C., M. Six, A.S., C.B., G.S.-F., R.K.) and the Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna (H.G., B.G., M. Schalling, R.K.) - both in Vienna; and the Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo (E.R., D.P., C.M., I.C.C., E.S., V.F., C.E., L.M., C.P., M.C.), and the Department of Molecular Medicine, University of Pavia (L.M., M.C.) - both in Pavia, Italy.
authors: Thorsten
authors: T
authors: Klampfl
authors: Heinz
authors: H
authors: Gisslinger
authors: Ashot S
authors: AS
authors: Harutyunyan
authors: Harini
authors: H
authors: Nivarthi
authors: Elisa
authors: E
authors: Rumi
authors: Jelena D
authors: JD
authors: Milosevic
authors: Nicole C C
authors: NC
authors: Them
authors: Tiina
authors: T
authors: Berg
authors: Bettina
authors: B
authors: Gisslinger
authors: Daniela
authors: D
authors: Pietra
authors: Doris
authors: D
authors: Chen
authors: Gregory I
authors: GI
authors: Vladimer
authors: Klaudia
authors: K
authors: Bagienski
authors: Chiara
authors: C
authors: Milanesi
authors: Ilaria Carola
authors: IC
authors: Casetti
authors: Emanuela
authors: E
authors: Sant'Antonio
authors: Virginia
authors: V
authors: Ferretti
authors: Chiara
authors: C
authors: Elena
authors: Fiorella
authors: F
authors: Schischlik
authors: Ciara
authors: C
authors: Cleary
authors: Melanie
authors: M
authors: Six
authors: Martin
authors: M
authors: Schalling
authors: Andreas
authors: A
authors: Schönegger
authors: Christoph
authors: C
authors: Bock
authors: Luca
authors: L
authors: Malcovati
authors: Cristiana
authors: C
authors: Pascutto
authors: Giulio
authors: G
authors: Superti-Furga
authors: Mario
authors: M
authors: Cazzola
authors: Robert
authors: R
authors: Kralovics
mesh_terms: D001855:Bone Marrow Diseases / Q000235:genetics; D037282:Calreticulin / Q000235:genetics*; D005091:Exons; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics; D009154:Mutation; D016133:Polymerase Chain Reaction; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000401:mortality; D016016:Proportional Hazards Models; D053628:Receptors, Thrombopoietin / Q000235:genetics; D017422:Sequence Analysis, DNA; D013920:Thrombocythemia, Essential / Q000150:complications / Q000235:genetics* / Q000401:mortality; D013927:Thrombosis / Q000209:etiology
chemical_list: D037282:Calreticulin; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2