Looking for CALR mutations in familial myeloproliferative neoplasms

Diseases commonly referred to as chronic myeloproliferative neoplasms (MPNs) comprise essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF) and chronic myeloid leukemia (CML), and are acquired, clonal disorders arising at the stem-cell level characterized by overproduction of terminally differentiated myeloid cells and a variable propensity to transform into acute leukemia.1 Although the underlying genetic defect in CML has been known for different decades, the genetic complexity of Philadelphia-negative MPNs has only more recently been unraveled. The somatic gain-of-function mutation JAK2V617F has been described in the vast majority of patients with PV and in 50-60% of those with ET and PMF. Subsequently, several additional mutations have been reported in a fraction of MPN patients (that is, mutations in JAK2 exon 12, MPL, CBL, TET2, DNMT3A, IDH1/2, EZH2 and ASXL1, among others). Very recently, two seminal publications reported on new mutations in the CALR gene in a substantial proportion of sporadic ET and PMF patients lacking the JAK2V617F mutation.