Mutant calreticulin neoepitope (mutCALR neoepitope)

Mutant calreticulin (mutCALR) neoepitope is a tumor-specific protein sequence resulting from frameshift mutations in exon 9 of the calreticulin gene (Nangalia et al., 2013, NEJM). These mutations occur in approximately 25-35% of patients with essential thrombocythemia and primary myelofibrosis, creating a unique, positively charged C-terminal tail that is absent in healthy tissues (Klampfl et al., 2013, NEJM). This neoepitope is highly immunogenic and serves as a specific marker for malignant clones, making it an ideal target for immunotherapy (Holmström et al., 2018, Leukemia). Mechanistically, the mutant protein escapes the endoplasmic reticulum and binds to the thrombopoietin receptor (MPL) on the cell surface or within the secretory pathway. This binding triggers constitutive activation of the JAK-STAT signaling pathway, which drives the overproduction of megakaryocytes and platelets (Araki et al., 2016, Blood). Therapeutic strategies currently under investigation include monoclonal antibodies like INCA033989, which block the mutCALR-MPL interaction, as well as peptide vaccines and TCR-T cell therapies designed to elicit a targeted immune response against mutant cells (Incyte, 2023; Rezk et al., 2023, Blood).

Other names

CALR exon 9 mutationmutCALRCalreticulin mutant neoantigenFrameshifted calreticulin

Therapeutic agents target the mutant calreticulin neoepitope to disrupt its interaction with the thrombopoietin receptor (MPL), thereby inhibiting constitutive JAK-STAT signaling and inducing immune-mediated destruction of mutant cells (Araki et al., 2016, Blood; Incyte, 2023).