Mutant calreticulin–directed immunotherapies in myeloproliferative neoplasms

Mutations in calreticulin (<i>CALR</i>) represent the second most common oncogenic driver of myeloproliferative neoplasms. <i>CALR</i> mutations result in the introduction of a neomorphic C-terminal tail that is absent from the normal proteome, which has positioned it as a compelling target for immunotherapeutic intervention. Early studies have demonstrated mutant CALR can elicit T-cell responses, laying the foundation for efforts to exploit this vulnerability through vaccines, antibody-based strategies, and T-cell-based therapies. Here, we summarize the current understanding of normal and mutant CALR biology, discuss progress in developing CALR-directed immunotherapies, and highlight the challenges and opportunities for translating these approaches into the clinic.