Mutant calreticulin-thrombopoietin receptor complex (mutCALR-MPL complex)

The mutant calreticulin-thrombopoietin receptor (mutCALR-MPL) complex is a pathogenic molecular assembly that drives the development of certain myeloproliferative neoplasms (MPNs), including essential thrombocythemia and primary myelofibrosis [4, 7]. Mutations in the CALR gene, typically insertions or deletions in exon 9, result in a frameshift that generates a novel, positively charged C-terminus neoepitope and causes the loss of the protein's KDEL endoplasmic reticulum (ER) retention signal [1, 11]. This mutant calreticulin protein (mutCALR) aberrantly binds to the extracellular domain of the thrombopoietin receptor (MPL, also known as TPO-R) within the secretory pathway [8, 18]. The resulting mutCALR-MPL complex traffics to the cell surface, where mutCALR induces constitutive, ligand-independent dimerization and activation of the receptor [9, 17]. This leads to hyperactivation of the Janus kinase 2 (JAK2) and signal transducer and activator of transcription (STAT) signaling pathways, promoting the uncontrolled proliferation of megakaryocytes and hematopoietic stem cells [10, 12]. Because the C-terminus neoepitope is entirely absent from the normal human proteome, it serves as a highly specific neoantigen for therapeutic intervention [13, 16]. Targeted therapies, such as the monoclonal antibody INCA033989, are designed to bind this neoepitope, disrupting the oncogenic complex and inhibiting downstream signaling while sparing healthy cells [2, 5, 22].

Other names

Mutant calreticulin neoepitope C-terminus on mutCALR–MPL/TPO-R complexmutCALR-TPO-R complexCALR-mutant MPL complexMutant calreticulin neoantigenmutCALR-MPL oncogenic complex

Selective binding to the mutant calreticulin C-terminus neoepitope to disrupt the mutCALR-MPL complex and inhibit constitutive JAK-STAT signaling.