Mutated calreticulin (CALR) (CALR)

Mutated calreticulin (CALR) is a primary driver of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia and primary myelofibrosis (Nangalia et al., NEJM, 2013). While wild-type calreticulin functions as an endoplasmic reticulum chaperone responsible for calcium buffering and protein quality control (UniProt P27797), mutations in exon 9 generate a novel, positively charged C-terminal tail (Klampfl et al., NEJM, 2013). This mutant tail enables calreticulin to bind to and constitutively activate the thrombopoietin receptor (MPL), even in the absence of its natural ligand (Araki et al., Blood, 2016). This interaction leads to the chronic activation of the JAK-STAT signaling pathway, driving the overproduction of megakaryocytes and subsequent bone marrow fibrosis (Chifotides et al., J Hem Onco, 2019). Because the mutant C-terminus is a neoantigen absent in normal tissues, it is an ideal target for precision therapies such as monoclonal antibodies and peptide vaccines currently in clinical development (ClinicalTrials.gov NCT05417126).

Other names

CALR mutationCalregulinCRP55HACBPERp60Mutant CALRCALR exon 9 mutation

Mutant CALR binds to and constitutively activates the thrombopoietin receptor (MPL), triggering the JAK-STAT pathway; therapeutic strategies include JAK2 inhibition or direct targeting of the mutant C-terminal neoantigen (Araki et al., Blood, 2016; ClinicalTrials.gov NCT05417126).