Mutant calreticulin–thrombopoietin receptor complex (Mutant CALR–MPL complex) (Mutant CALR–MPL complex)

The mutant calreticulin–thrombopoietin receptor (MPL) complex is a pathological protein assembly central to the pathogenesis of certain myeloproliferative neoplasms (MPNs), including essential thrombocythemia and primary myelofibrosis (Nangalia et al., 2013, NEJM; Klampfl et al., 2013, NEJM). In these conditions, mutations in exon 9 of the CALR gene result in a novel C-terminal peptide that allows the mutant calreticulin protein to bind specifically to the thrombopoietin receptor (MPL) (Araki et al., 2016, Blood). This interaction occurs within the secretory pathway and leads to the trafficking of the complex to the cell surface, where it induces constitutive, ligand-independent activation of the JAK-STAT signaling pathway (Chachoua et al., 2016, Blood). This aberrant signaling drives the uncontrolled proliferation of megakaryocytes and other myeloid cells. Therapeutic strategies targeting this complex include JAK inhibitors like ruxolitinib, which block downstream signaling, and emerging monoclonal antibodies, such as INCA033989, designed to specifically recognize the mutant CALR protein or the complex itself (Incyte, 2023; Reis et al., 2022, Nature Communications). By disrupting this interaction or depleting cells expressing the mutant complex, these therapies aim to restore normal hematopoiesis and reduce the disease burden in MPN patients.

Other names

Mutant CALR–TPO-R complexCALR-mutant MPL complexMutant calreticulin–MPL complexMutant CALR–thrombopoietin receptor complex

Inhibition of the JAK-STAT signaling pathway downstream of the constitutively active complex, or direct targeting of the mutant CALR protein to prevent its interaction with and activation of the MPL receptor (Araki et al., 2016, Blood; Incyte, 2023).