• Thorsten Klampfl, Heinz Gisslinger, Ashot S Harutyunyan, Harini Nivarthi, Elisa Rumi, Jelena D Milosevic, Nicole C C Them, Tiina Berg, Bettina Gisslinger, Daniela Pietra, Doris Chen, Gregory I Vladimer, Klaudia Bagienski, Chiara Milanesi, Ilaria Carola Casetti, Emanuela Sant'Antonio, Virginia Ferretti, Chiara Elena, Fiorella Schischlik, Ciara Cleary, Melanie Six, Martin Schalling, Andreas Schönegger, Christoph Bock, Luca Malcovati, Cristiana Pascutto, Giulio Superti-Furga, Mario Cazzola, and Robert Kralovics.
• 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.
• N. Engl. J. Med. 2013 Dec 19; 369 (25): 2379-90.

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.).

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