Mutated calreticulin retains structurally disordered C terminus that cannot bind Ca2+: some mechanistic and therapeutic implications

Two very recent reports1, 2 made a tremendous breakthrough in our understanding of the molecular basis of myeloproliferative neoplasms (MPNs) without mutations in Janus kinase 2 (JAK2) and myeloproliferative leukemia (MPL) virus oncogene genes. Klampfl et al.1 and Nangalia et al.2 independently identified recurrent somatic mutation in the calreticulin (CALR) gene exclusively in patients with JAK2 and MPL mutation-negative MPNs. Strikingly, all these mutations were small deletions and insertions in exon 9 of the gene leading to a shift in the open reading frame and expression of peptides in which the wild-type C terminus was substituted for a novel identical in all mutants C terminus and a small mutant-specific portion of variable length. This specific feature of CALR mutations necessitates further elucidation of the mechanisms through which they promote neoplastic transformation and might be particularly challenging to dissect as CALR is involved in a plethora of intra- and extra-endoplasmic reticulum (ER) cellular processes.3