Mutant calreticulin neoantigen (CALR-mut neoantigen)

Mutant calreticulin (CALR) neoantigens arise from frameshift mutations in exon 9 of the CALR gene, which are found in approximately 25-35% of patients with essential thrombocythemia and primary myelofibrosis. These mutations result in a novel, highly basic C-terminal peptide sequence that is shared across patients and is absent in healthy individuals, making it an ideal tumor-specific neoantigen. Biologically, the mutant CALR protein binds to and constitutively activates the thrombopoietin receptor (MPL), driving the JAK-STAT signaling pathway and malignant hematopoiesis. Because the frameshifted C-terminus is extracellularly accessible or presented as a peptide on HLA molecules, it is being targeted by various immunotherapeutic modalities. Current drug development efforts include monoclonal antibodies that neutralize the mutant protein's oncogenic signaling and T-cell-based therapies or vaccines aimed at eradicating the malignant clone by recognizing the neoantigenic sequence.

Other names

CALR exon 9 mutantFrameshifted calreticulinCALR-mutant C-terminusMutated calreticulin

Therapeutic strategies targeting mutant calreticulin neoantigens include monoclonal antibodies that block the interaction between mutant CALR and the thrombopoietin receptor (MPL), thereby inhibiting constitutive JAK-STAT signaling, as well as cancer vaccines and TCR-engineered T-cells designed to induce a cytotoxic immune response against cells presenting the frameshifted C-terminal peptide on HLA molecules.