Mutant calreticulin (CALR) neoantigen (Mutant CALR)

Mutant calreticulin (CALR) is a primary oncogenic driver in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), specifically essential thrombocythemia and primary myelofibrosis (Nangalia et al., 2013; Klampfl et al., 2013). Frameshift mutations in exon 9 of the CALR gene generate a novel, positively charged C-terminal tail that is entirely distinct from the wild-type protein. This mutant tail functions as a neoantigen and induces the constitutive activation of the thrombopoietin receptor (MPL), which triggers the JAK-STAT signaling pathway and promotes uncontrolled neoplastic cell proliferation (Araki et al., 2016; Chachoua et al., 2016). Because this neoantigen is highly specific to the malignant clone and is expressed on the cell surface, it represents an ideal target for selective immunotherapy. Current drug development efforts focus on monoclonal antibodies, such as INCA033989, that disrupt the mutant CALR-MPL interaction to normalize signaling (Incyte, 2024). Additionally, cancer vaccines and CAR-T cell therapies are being designed to exploit the neoantigen's immunogenicity to eliminate the malignant cells while sparing healthy hematopoiesis (NCT03566446; Pesini et al., 2026).

Other names

CALR exon 9 mutationmutCALRCALR neoepitopeCALR frameshift mutationMutant calreticulin novel C-terminus

Selective antagonism of the mutant CALR-MPL interaction to inhibit constitutive JAK-STAT signaling and induction of T-cell mediated cytotoxicity against neoantigen-expressing cells (Incyte, 2024; Holmström et al., 2018).