New Gene Mutation Identified in Myeloproliferative Neoplasms

Jayson Slotnik, JD, MPH

February 2014, Vol 5, No 1 - In the Literature


New research shows promise in deciphering the underlying mechanism of myeloproliferative neoplasms (MPNs), according to findings from a recently reported study (Klampfl T, et al. N Engl J Med. 2013;369:2379-2390).

The Janus kinase 2 (JAK2) gene is present in approximately 50% to 60% of patients with essential thrombocythemia or primary myelofibrosis, and an additional 5% to 10% have activating mutations in the thrombopoietin receptor gene, MPL. However, no specific molecular marker has been identified in the remaining 30% to 45% of patients.

In the study, Klampfl and colleagues performed whole-exome sequencing and identified somatically acquired mutations in 6 patients with primary myelofibrosis without JAK2 or MPL mutations. After confirming the presence of 2 to 12 somatic mutations per patient, the analysis revealed recurrent somatic insertions and deletions in exon 9 of CALR, encoding calreticulin. The researchers resequenced 1107 samples from patients with MPN and found that CALR mutations were absent in polycythemia vera; however, CALR mutations and JAK2 and MPL mutations were mutually exclusive in essential thrombocythemia and primary myelofibrosis. Among patients with essential thrombocythemia and primary myelofibrosis with wild-type JAK2 or MPL, the researchers identified CALR mutations in 67% and 88% of patients, respectively. The researchers detected 36 different types of mutations in CALR. The prevalent types were a 52-bp deletion and a 5-bp insertion (53% and 31.7%, respectively). The findings also showed that patients with mutated CALR had a lower risk of thrombosis and longer OS than patients with mutated JAK2. Patients with primary myelofibrosis and a somatic mutation of CALR had longer OS than those with a JAK2 mutation (median, 21.4 years vs 11 years, respectively; P <.001). The OS rates at 10 years among patients with essential thrombocythemia were 96.9% in patients with a CALR mutation and 91.1% in patients with a JAK2 mutation (P = .04). Patients with a CALR exon 9 mutation had a lower cumulative incidence of thrombosis at 10 years than patients with the JAK2 mutation (11% vs 21%, respectively; P = .003).

From a practical point of view, the researchers suggested that different effects of mutated genes might be incorporated into existing prognostic scoring systems and guide therapeutic decision-making for patients with primary myelofibrosis and essential thrombocythemia. Furthermore, the CALR molecular characterization may become a critical component in the clinical management of these 2 types of MPN.