Mutant calreticulin exon 9 frameshift neoantigen (CALRmut)

Mutant calreticulin (CALR) exon 9 frameshift neoantigen is a tumor-specific protein variant resulting from somatic mutations in the CALR gene, predominantly found in patients with JAK2-wildtype myeloproliferative neoplasms (MPNs) (Nangalia et al., 2013, NEJM). These mutations, typically Type 1 (52-bp deletion) or Type 2 (5-bp insertion), cause a +1 frameshift that generates a novel, positively charged 36-amino acid C-terminal tail while losing the native endoplasmic reticulum retention signal (KDEL) (Klampfl et al., 2013, NEJM). This neoantigenic C-terminus allows the mutant protein to bind and constitutively activate the thrombopoietin receptor (MPL), driving the JAK-STAT signaling pathway and promoting oncogenic transformation of hematopoietic stem cells (Araki et al., 2016, Blood). Because the frameshifted C-terminal sequence is entirely unique to malignant cells and highly conserved across patients, it represents an ideal target for immunotherapy (Holmstrom et al., 2018, Leukemia). Therapeutic approaches currently under investigation include monoclonal antibodies like INCA033989 that neutralize the mutant protein's interaction with MPL and vaccines or T-cell therapies designed to recognize the neoantigenic peptides presented on the cell surface (Incyte, 2023). Targeting this neoantigen offers a high degree of specificity, potentially minimizing damage to healthy tissues that express only wild-type calreticulin.

Other names

CALR exon 9 mutationMutant CALR C-terminusCALR Type 1 mutationCALR Type 2 mutationCALR frameshift neoantigenCalreticulin mutant protein

Monoclonal antibodies or T-cell based therapies targeting the novel C-terminal sequence to inhibit MPL activation or induce immune-mediated cell death.