Mutant Calreticulin in MPN: Mechanistic Insights and Therapeutic Implications
Key claim: The mutant CALR–MPL complex forms a tetramer with the mutant CALR C-terminus exposed on the cell surface, providing structural insights with therapeutic implications for CALR-mutant MPN.
Abstract
More than a decade following the discovery of Calreticulin (CALR) mutations as drivers of myeloproliferative neoplasms, advances in the understanding of CALR-mutant MPN continue to emerge. Structural insights revealed that the mutant CALR-MPL complex is a tetramer and the mutant CALR C-terminus is exposed on the cell surface.
Why this matters
Structural characterization of the mutant CALR–MPL complex as a tetramer with the mutant C-terminus exposed on the cell surface provides the mechanistic foundation for the entire class of CALR-neoepitope-directed therapies now advancing in MPN. This explains why antibody (INCA033989, JNJ-88549968), bispecific (INCA035784), and vaccine approaches can all selectively engage CALR-mutant clones while sparing wild-type cells, and frames the rationale for clone-directed disease modification rather than symptom control.