Calreticulin Mutations Are Common in Myeloproliferative Neoplasms

The identification of activating mutations in JAK2 in almost all patients with polycythemia vera and JAK2 or MPL mutations in 55% to 70% of patients with essential thrombocythemia and myelofibrosis has simplified the diagnosis of these myeloproliferative neoplasms, but diagnosis remains difficult in the remaining 30% to 45% of patients who lack JAK2 or MPL mutations. Through a combination of exomic and targeted sequencing, Nangalia and colleagues identified somatic calreticulin (CALR) mutations in 70% of patients with essential thrombocythemia or myelofibrosis that lacked JAK2 or MPL mutations, and Klampfl and colleagues found CALR mutations in 73% of essential thrombocythemia or myelofibrosis with nonmutated JAK2 or MPL. CALR mutations were acquired early in the major clones of patient samples, providing support for a role in the initiation of myeloproliferative neoplasms. Every CALR mutation identified was a frameshift mutation within exon 9 that resulted in an expressed protein with a novel C-terminus that also lacked an endoplasmic reticulum-retention sequence, suggesting that the mutations affect CALR function and localization. Klampfl and colleagues also found that expression of the most common CALR mutant increased STAT5 phosphorylation and induced cytokine-independent growth that could be blocked by a JAK inhibitor, suggesting that CALR and JAK2 mutations may have similar consequences, although the mechanism by which mutant CALR activates JAK–STAT signaling remains unclear. Both groups noted differences in hemoglobin levels and platelet counts between patients with CALR and JAK2 mutations, and Klampfl and colleagues found that patients with CALR mutations had a significantly longer overall survival, suggesting that CALR mutations may also have clinical and prognostic significance. The identification of CALR as a frequently mutated gene in essential thrombocythemia and myelofibrosis addresses a gap in the molecular diagnosis of myeloproliferative neoplasms and may have implications for management of these cancers.

Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013;369:2391–405.

Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369:2379–90.

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