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

Two very recent reports 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. and Nangalia et al. independently identified recurrent somatic mutation in the calreticulin (CALR) gene exclusively in patients with JAK2 and MPLmutation-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 intraand extra-endoplasmic reticulum (ER) cellular processes. However, as pointed by the two reports, the C terminus of the wild-type CALR has three important features: (i) its secondary structure is disordered; (ii) it is acidic and binds calcium ions at low affinity; (iii) it has an ER retention signal. Both Klampfl et al. and Nangalia et al. reported the loss of C-terminal ER retention signal (KDEL) in the mutant proteins. However, both groups did not observe significant changes in the subcellular distribution of mutant CALR protein as compared with the wild type. A possible explanation for their observation would be that as reported previously, CALR retro-translocation from ER to the cytoplasm is also dependent on the C-terminal domain.