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Purpose of Review <p>More than a decade following the discovery of <i>Calreticulin (CALR)</i> mutations as drivers of myeloproliferative neoplasms (MPN), advances in the understanding of <i>CALR</i>-mutant MPN continue to emerge. Here, we summarize recent advances in mehanistic understanding and in targeted therapies for <i>CALR</i>-mutant MPN.</p> Recent Findings <p>Structural insights revealed that the mutant CALR-MPL complex is a tetramer and the mutant CALR C-terminus is exposed on the cell surface. Targeting mutant CALR utilizing antibodies is the leading therapeutic approach, while mutant CALR-directed vaccines are also in early clinical trials. Additionally, chimeric antigen receptor (CAR) T-cells directed against mutant CALR are under evaluation in preclinical models. Approaches addressing the cellular effects of mutant CALR beyond MPL-JAK-STAT activation, such as targeting the unfolded protein response, proteasome, and <i>N</i>-glycosylation pathways, have been tested in preclinical models.</p> Summary <p>In <i>CALR</i>-mutant MPN, the path from discovery to mechanistic understanding to direct therapeutic targeting has advanced rapidly. The longer-term goal remains clonally-selective therapies that modify the disease course in patients.</p>

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Mutant Calreticulin in MPN: Mechanistic Insights and Therapeutic Implications

  • 期刊论文

  • 发表日期：

    2025年1月8日

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  • Mifra Faiz,
  • Merle Riedemann,
  • Jonas S. Jutzi,
  • Ann Mullally

摘要

Purpose of Review

More than a decade following the discovery of Calreticulin (CALR) mutations as drivers of myeloproliferative neoplasms (MPN), advances in the understanding of CALR-mutant MPN continue to emerge. Here, we summarize recent advances in mehanistic understanding and in targeted therapies for CALR-mutant MPN.

Recent Findings

Structural insights revealed that the mutant CALR-MPL complex is a tetramer and the mutant CALR C-terminus is exposed on the cell surface. Targeting mutant CALR utilizing antibodies is the leading therapeutic approach, while mutant CALR-directed vaccines are also in early clinical trials. Additionally, chimeric antigen receptor (CAR) T-cells directed against mutant CALR are under evaluation in preclinical models. Approaches addressing the cellular effects of mutant CALR beyond MPL-JAK-STAT activation, such as targeting the unfolded protein response, proteasome, and N-glycosylation pathways, have been tested in preclinical models.

Summary

In CALR-mutant MPN, the path from discovery to mechanistic understanding to direct therapeutic targeting has advanced rapidly. The longer-term goal remains clonally-selective therapies that modify the disease course in patients.