Mutant calreticulin – thrombopoietin receptor interface (Mutant CALR-MPL interface)

The mutant calreticulin (CALR) – thrombopoietin receptor (MPL) interface is a pathological protein-protein interaction that drives the development of myeloproliferative neoplasms (MPNs), specifically essential thrombocythemia and primary myelofibrosis (Nivarthi et al., 2016, Blood). In these diseases, frameshift mutations in exon 9 of the CALR gene create a novel, positively charged C-terminal domain that replaces the KDEL endoplasmic reticulum-retention signal (Araki et al., 2016, Blood). This mutant CALR protein physically associates with the extracellular domain of the thrombopoietin receptor (MPL), leading to its constitutive activation (Elf et al., 2016, Cancer Discovery). This interaction triggers the JAK-STAT signaling pathway independently of the natural ligand thrombopoietin, resulting in the overproduction of megakaryocytes and platelets. Because the interaction depends on the unique neo-epitope of the mutant CALR C-terminus, it provides a highly specific therapeutic window for drug intervention. Therapeutic strategies currently under investigation include monoclonal antibodies, such as INCA033989, which are designed to block this interface and inhibit oncogenic signaling while minimizing effects on normal hematopoietic processes (Incyte, 2023).

Other names

Mutant CALR-MPL complexCALR mutant-TPO receptor interactionMutant calreticulin-MPL signaling complexMutant CALR-MPL interface

Disruption of the pathogenic interaction between the mutant calreticulin C-terminus and the extracellular domain of the thrombopoietin receptor to inhibit constitutive JAK-STAT activation.