Mutant calreticulin neoepitope at the mutant calreticulin–thrombopoietin receptor interface (mutCALR–TpoR interface)

Mutant calreticulin (mutCALR) is a primary driver of myeloproliferative neoplasms (MPNs), including essential thrombocythemia and primary myelofibrosis (Nangalia et al., 2013). Mutations in exon 9 of the CALR gene cause a frameshift that produces a unique, positively charged C-terminal neoepitope that is shared across different mutation types (Klampfl et al., 2013). This mutant protein is secreted or expressed on the cell surface, where it binds to and dimerizes the thrombopoietin receptor (TpoR/MPL) through a specific protein-protein interface (Araki et al., 2016). This interaction results in the constitutive activation of the JAK-STAT signaling pathway, leading to the overproduction of megakaryocytes and platelets. Therapeutic strategies focus on using monoclonal antibodies, such as INCA033989, to target the mutCALR neoepitope or the mutCALR–TpoR interface, effectively neutralizing the oncogenic signal while minimizing effects on healthy cells that lack the mutation (Elf et al., 2016; Incyte, 2023).

Other names

mutCALR-MPL interfaceCALR neoepitopeMutant calreticulin C-terminal neoantigenmutCALR-TpoR complexCALR-mutant/MPL complex

Monoclonal antibody-mediated blockade of the interaction between the mutant calreticulin C-terminal neoepitope and the thrombopoietin receptor (TpoR/MPL), thereby inhibiting constitutive JAK-STAT signaling (Elf et al., 2016; Incyte, 2023).