Calreticulin and myeloproliferative neoplasms: linking biology to targeted therapies

Calreticulin (CALR) plays important roles in protein homeostasis, immune responses, and cell signaling. Mutations in the CALR gene drive BCR:ABL1-negative classical myeloproliferative neoplasms (MPNs) through constitutive activation of the thrombopoietin receptor and generate a tumor-specific neoepitopes, providing a rationale for selective immunotherapy.

This review summarizes the biological functions of wild-type calreticulin and the molecular consequences of mutant calreticulin, including loss of endoplasmic reticulum retention, altered subcellular localization, receptor activation, and immunogenic properties. It examines preclinical and clinical evidence for therapeutic strategies targeting mutant calreticulin, including peptide-based vaccines, monoclonal antibodies, T-cell engagers, and chimeric antigen receptor T-cell therapies. Particular attention is given to INCA033989, a mutant calreticulin-targeting monoclonal antibody currently undergoing clinical evaluation, and emerging evidence of its potential to reduce the mutant cell population while preserving normal hematopoiesis.

Mutant calreticulin represents a promising target for clone-directed therapy, potentially shifting MPN treatment from symptom control toward disease modification. However, the durability and clinical significance of molecular responses remain uncertain. Immune evasion, differences between mutation subtypes, and the need to demonstrate long-term clinical benefit remain important challenges. Combining calreticulin-targeted therapies with approaches addressing oncogenic signaling and inflammation may improve treatment durability and help prevent disease progression.