Mutations in calreticulin are one of the key disease-initiating mutations in myeloproliferative neoplasms (MPN). In MPN, mutant calreticulin translates with a novel C-terminus that leads to aberrant binding to the extracellular domain of the thrombopoietin receptor, MPL. This cell surface neoantigen has become an attractive target for immunological intervention. Here, we summarize recent advances in the development of mutant calreticulin targeting antibodies as a novel therapeutic approach in MPN.
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| http://dx.doi.org/10.1111/jcmm.17896 | DOI Listing |
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Impact of calreticulin mutations on treatment and survival outcomes in myelofibrosis during ruxolitinib therapy.
Ann Hematol
January 2025
Department of Engineering for Innovation Medicine, Section of Innovation Biomedicine, Hematology Area, University of Verona, Verona, Italy.
Calreticulin (CALR) mutations are detected in around 20% of patients with primary and post-essential thrombocythemia myelofibrosis (MF). Regardless of driver mutations, patients with splenomegaly and symptoms are generally treated with JAK2-inhibitors, most commonly ruxolitinib. Recently, new therapies specifically targeting the CALR mutant clone have entered clinical investigation.
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Curr Hematol Malig Rep
January 2025
Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
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.
The aberrantly activated AURKB supports and complements the function of AURKA in CALR mutated cells through regulating the cell growth and differentiation.
Exp Cell Res
January 2025
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China. Electronic address:
Aurora kinase B (AURKB) was reported to assist Aurora kinase A (AURKA) to regulate cellular mitosis. AURKA has been found activated in myeloproliferative neoplasms (MPNs) patients with CALR gene mutation, however, it's unclear whether AURKB displays a compensatory function of AURKA in regulation of CALR mutant cell growth and differentiation. Here, we found that AURKB, similar with AURKA, was aberrantly activated in CALR mutant patients, and displayed a more tolerance to the aurora kinase inhibitor.
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Hemasphere
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Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty RWTH Aachen University Aachen Germany.
Myelofibrosis (MF) is a clonal myeloid neoplasm characterized by bone marrow fibrosis, splenomegaly, and disease-associated symptoms, as well as increased mortality, due to thrombosis, severe bleeding, infections, or progression to acute leukemia. Currently, the management of MF patients is tailored according to risk scores, with higher-risk (intermediate-2 and high-risk) patients being assessed for allogeneic stem cell transplantation, which remains the only potentially curative treatment option. On the other hand, lower risk (low- and intermediate-1 risk) patients who are symptomatic may be treated with JAK inhibitors or other drugs.
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Asian Pac J Cancer Prev
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Cytogenetics Laboratory, Pasteur Institute of Morocco (IPM), 1 Place Louis Pasteur, 20360 Casablanca, Morocco.
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