Calreticulin–Thrombopoietin receptor protein–protein interface (CALR–MPL interface)

The Calreticulin–Thrombopoietin receptor (CALR–MPL) protein–protein interface is a pathological interaction central to the pathogenesis of CALR-mutated myeloproliferative neoplasms (MPNs), including essential thrombocythemia and primary myelofibrosis (Nangalia et al., 2013, NEJM). In these diseases, frameshift mutations in exon 9 of the CALR gene create a novel, positively charged C-terminal tail that enables mutant CALR to bind to the extracellular domain of MPL (Araki et al., 2016, Blood). This interaction leads to the constitutive, ligand-independent activation of MPL and the downstream JAK-STAT signaling pathway, driving uncontrolled megakaryopoiesis and platelet production (Elf et al., 2016, Cancer Discovery). Because this interface is unique to malignant cells harboring the CALR mutation, it represents a highly specific therapeutic target for precision medicine. Current drug development efforts, such as the monoclonal antibody INCA033989, aim to disrupt this binding to inhibit oncogenic signaling while sparing normal hematopoietic processes (Incyte, 2023, ASH Annual Meeting). Targeting this interface may provide a more selective alternative to broad JAK inhibitors, potentially reducing systemic toxicities.

Other names

Mutant CALR-MPL complexCALR-MPL interaction siteCalreticulin-Myeloproliferative leukemia protein interfacemutCALR-MPL interface

Inhibition of the protein-protein interaction between mutant calreticulin and the thrombopoietin receptor (MPL), thereby preventing constitutive JAK2/STAT signaling.