Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms

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...

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Published inThe 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
LanguageEnglish
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
Online AccessGet full text

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Abstract 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 . . .
AbstractList 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. 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. 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. 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.).
BackgroundApproximately 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.MethodsWe 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.ResultsSomatic 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.ConclusionsMost 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.)
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 . . .
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.BACKGROUNDApproximately 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.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.METHODSWe 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.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.RESULTSSomatic 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.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.).CONCLUSIONSMost 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.).
Author Rumi, Elisa
Bagienski, Klaudia
Pascutto, Cristiana
Bock, Christoph
Them, Nicole C.C
Elena, Chiara
Pietra, Daniela
Milanesi, Chiara
Nivarthi, Harini
Harutyunyan, Ashot S
Milosevic, Jelena D
Vladimer, Gregory I
Sant'Antonio, Emanuela
Ferretti, Virginia
Malcovati, Luca
Schalling, Martin
Berg, Tiina
Gisslinger, Bettina
Schönegger, Andreas
Klampfl, Thorsten
Cleary, Ciara
Superti-Furga, Giulio
Gisslinger, Heinz
Schischlik, Fiorella
Cazzola, Mario
Six, Melanie
Kralovics, Robert
Casetti, Ilaria Carola
Chen, Doris
Author_xml – sequence: 1
  givenname: Thorsten
  surname: Klampfl
  fullname: Klampfl, Thorsten
  organization: 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
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  givenname: Heinz
  surname: Gisslinger
  fullname: Gisslinger, Heinz
  organization: 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
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  organization: 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
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  organization: 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
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  givenname: Jelena D
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  givenname: Nicole C.C
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  organization: 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
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  givenname: Tiina
  surname: Berg
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  organization: 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
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  organization: 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
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  surname: Pietra
  fullname: Pietra, Daniela
  organization: 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
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  givenname: Doris
  surname: Chen
  fullname: Chen, Doris
  organization: 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
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  givenname: Gregory I
  surname: Vladimer
  fullname: Vladimer, Gregory I
  organization: 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
– sequence: 13
  givenname: Klaudia
  surname: Bagienski
  fullname: Bagienski, Klaudia
  organization: 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
– sequence: 14
  givenname: Chiara
  surname: Milanesi
  fullname: Milanesi, Chiara
  organization: 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
– sequence: 15
  givenname: Ilaria Carola
  surname: Casetti
  fullname: Casetti, Ilaria Carola
  organization: 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
– sequence: 16
  givenname: Emanuela
  surname: Sant'Antonio
  fullname: Sant'Antonio, Emanuela
  organization: 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
– sequence: 17
  givenname: Virginia
  surname: Ferretti
  fullname: Ferretti, Virginia
  organization: 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
– sequence: 18
  givenname: Chiara
  surname: Elena
  fullname: Elena, Chiara
  organization: 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
– sequence: 19
  givenname: Fiorella
  surname: Schischlik
  fullname: Schischlik, Fiorella
  organization: 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
– sequence: 20
  givenname: Ciara
  surname: Cleary
  fullname: Cleary, Ciara
  organization: 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
– sequence: 21
  givenname: Melanie
  surname: Six
  fullname: Six, Melanie
  organization: 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
– sequence: 22
  givenname: Martin
  surname: Schalling
  fullname: Schalling, Martin
  organization: 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
– sequence: 23
  givenname: Andreas
  surname: Schönegger
  fullname: Schönegger, Andreas
  organization: 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
– sequence: 24
  givenname: Christoph
  surname: Bock
  fullname: Bock, Christoph
  organization: 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
– sequence: 25
  givenname: Luca
  surname: Malcovati
  fullname: Malcovati, Luca
  organization: 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
– sequence: 26
  givenname: Cristiana
  surname: Pascutto
  fullname: Pascutto, Cristiana
  organization: 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
– sequence: 27
  givenname: Giulio
  surname: Superti-Furga
  fullname: Superti-Furga, Giulio
  organization: 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
– sequence: 28
  givenname: Mario
  surname: Cazzola
  fullname: Cazzola, Mario
  organization: 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
– sequence: 29
  givenname: Robert
  surname: Kralovics
  fullname: Kralovics, Robert
  organization: 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
BackLink http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28001919$$DView record in Pascal Francis
https://www.ncbi.nlm.nih.gov/pubmed/24325356$$D View this record in MEDLINE/PubMed
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CODEN NEJMAG
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SSID ssj0000149
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Snippet The authors identified calreticulin mutations in the majority of patients with essential thrombocythemia and myelofibrosis who did not have JAK2 mutations. The...
Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an...
BackgroundApproximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and...
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SubjectTerms 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
Title Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms
URI https://nejm.org/doi/full/10.1056/NEJMoa1311347
https://www.ncbi.nlm.nih.gov/pubmed/24325356
https://www.proquest.com/docview/1469702357
https://www.proquest.com/docview/1490731949
Volume 369
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