Mutant calreticulin (CALRmut) (CALRmut)

Mutant calreticulin (CALRmut) is a primary driver of myeloproliferative neoplasms (MPNs), including essential thrombocythemia and primary myelofibrosis. These mutations, primarily occurring in exon 9, cause a frameshift that generates a unique, positively charged C-terminal neoantigen and removes the KDEL endoplasmic reticulum retention signal (Nangalia et al., 2013; Klampfl et al., 2013). The resulting mutant protein gains a neomorphic function by binding to and constitutively activating the thrombopoietin receptor (MPL), which leads to chronic JAK-STAT signaling and abnormal blood cell production (Araki et al., 2016). Because the mutant C-terminus is entirely absent in healthy tissues, it serves as a highly specific therapeutic target and a potent neoantigen for the immune system (Holmström et al., 2018). Current therapeutic strategies include JAK2 inhibitors to manage symptoms, as well as novel approaches like monoclonal antibodies (e.g., INCA033989) and peptide vaccines designed to specifically eliminate CALR-mutant clones (Incyte, 2023; ClinicalTrials.gov). This target represents a significant advancement in precision oncology for hematologic malignancies.

Other names

CALR exon 9 mutationMutant CALRCalreticulin exon 9 mutantCALR frameshift mutation

Direct binding to the mutant C-terminus to block MPL interaction or indirect inhibition of the downstream JAK-STAT signaling pathway.