Calreticulin–Myeloproliferative leukemia protein signaling complex (CALR–MPL complex)

The Calreticulin–Myeloproliferative leukemia protein (CALR–MPL) signaling complex is a pathological protein-protein assembly that drives the pathogenesis of certain myeloproliferative neoplasms (MPNs). In patients with essential thrombocythemia or primary myelofibrosis, frameshift mutations in exon 9 of the CALR gene produce a mutant protein with a unique, positively charged C-terminal tail (Araki et al., 2016; Blood). This mutant CALR tail physically binds to the extracellular domain of the MPL receptor (thrombopoietin receptor), leading to its constitutive, ligand-independent dimerization and activation (Chachoua et al., 2016; Blood). This interaction results in chronic activation of the JAK-STAT signaling pathway, which promotes the uncontrolled proliferation and differentiation of megakaryocytes (Elf et al., 2016; Cancer Discovery). Because the complex is uniquely formed by the mutant version of CALR, it serves as a highly specific therapeutic target. Current drug development efforts include monoclonal antibodies like INCA033989, which are designed to disrupt the CALR-MPL interaction and restore normal hematopoiesis (Incyte, 2023). Targeting this complex offers a precision medicine approach to treating MPNs while potentially minimizing effects on healthy cells that lack the mutation.

Other names

Mutant CALR–MPL complexCALR–TPO-R complexCalreticulin–Thrombopoietin receptor complexMutant calreticulin–MPL signaling complex

Monoclonal antibodies (e.g., INCA033989) specifically bind to the mutant C-terminus of calreticulin, preventing its interaction with the extracellular domain of the MPL receptor and thereby blocking constitutive JAK-STAT signaling. Small molecule JAK inhibitors (e.g., Ruxolitinib) act downstream of the complex to inhibit the kinase activity triggered by the CALR-MPL interaction.