Mutant Calreticulin in MPN: Mechanistic Insights and Therapeutic Implications
- 01-12-2025
- Review
Published in:
- Authors
- Mifra Faiz
- Merle Riedemann
- Jonas S. Jutzi
- Ann Mullally
- Published in
- Current Hematologic Malignancy Reports | Issue 1/2025
Abstract
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.
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- Title
- Mutant Calreticulin in MPN: Mechanistic Insights and Therapeutic Implications
- Authors
-
Mifra Faiz
Merle Riedemann
Jonas S. Jutzi
Ann Mullally
- Publication date
- 01-12-2025
- Publisher
- Springer US
- Published in
-
Current Hematologic Malignancy Reports / Issue 1/2025
Print ISSN: 1558-8211
Electronic ISSN: 1558-822X - DOI
- https://doi.org/10.1007/s11899-024-00749-4
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