Mutant calreticulin neoantigen C-terminus (mutCALR C-term) (mutCALR C-term)

Mutant calreticulin (mutCALR) neoantigen C-terminus refers to the novel protein sequence generated by frameshift mutations in exon 9 of the CALR gene, which are found in approximately 30% of patients with myeloproliferative neoplasms (MPNs) such as essential thrombocythemia and primary myelofibrosis (Nangalia et al., 2013, NEJM). These mutations result in the loss of the C-terminal KDEL endoplasmic reticulum (ER) retention signal and the creation of a common, positively charged 36-amino acid tail (Klampfl et al., 2013, NEJM). This neoantigenic tail allows the mutant protein to escape the ER and bind to the thrombopoietin receptor (MPL), leading to constitutive activation of the JAK-STAT signaling pathway and driving malignant cell proliferation (Araki et al., 2016, Blood). Because this C-terminal sequence is entirely unique to the tumor cells and shared across different CALR mutation types, it represents an ideal target for immunotherapy (Schischlik et al., 2019, Blood). Therapeutic strategies currently in development include peptide-based vaccines, T-cell receptor (TCR) engineered T-cells, and monoclonal antibodies designed to specifically recognize and eliminate mutCALR-expressing clones (Zelluna Immunotherapy, 2023; Holmström et al., 2018, Leukemia). These approaches aim to provide a highly specific treatment for MPN patients while sparing normal hematopoietic cells.

Other names

CALR exon 9 mutation neoantigenmutant CALR C-terminal peptideCALR frameshift neoantigenmutant calreticulin

The primary mechanism of action for drugs targeting the mutant calreticulin C-terminus is the induction of a specific immune response, such as T-cell mediated cytotoxicity via vaccines or TCR-engineered T-cells, or the use of monoclonal antibodies to block the interaction between mutant calreticulin and the thrombopoietin receptor (MPL) (Boiocchi et al., 2022, Frontiers in Oncology; Schischlik et al., 2019, Blood).