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Using CRISPR/Cas9 Gene Editing to Investigate the Oncogenic Activity of Mutant Calreticulin in Cytokine Dependent Hematopoietic Cells
Published on: January 5, 2018
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Zinc-dependent multimerization of mutant calreticulin is required for MPL binding and MPN pathogenesis
Jeanne F Rivera1,2, April J Baral1, Fatima Nadat1
1School of Molecular and Cellular Biology, Faculty of Biological Sciences, and.
Blood Advances
|April 6, 2021
Summary
Zinc is essential for mutant calreticulin (CALRdel52) to drive myeloproliferative neoplasms by enabling multimerization and MPL receptor binding. Zinc chelation disrupts these complexes, offering a potential new therapeutic strategy for MPNs.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Calreticulin (CALR) mutations are prevalent in JAK2/MPL-unmutated myeloproliferative neoplasms (MPNs).
- Mutant CALR (CALRdel52) activates JAK-STAT signaling via the thrombopoietin receptor MPL.
Purpose of the Study:
- To identify critical motifs for CALRdel52 oncogenic activity.
- To investigate the role of zinc in CALRdel52-mediated oncogenesis.
- To explore zinc chelation as a therapeutic strategy for CALR-mutant MPNs.
Main Methods:
- Extensive mutagenesis screen of the CALR globular N-domain.
- Analysis of CALRdel52 multimerization and MPL binding.
- Treatment of hematopoietic cells and primary MPN erythroblasts with zinc chelators.
Main Results:
- The glycan-binding lectin motif and zinc-binding domain are critical for CALRdel52 oncogenicity.
- The zinc-binding domain is essential for CALRdel52 homomultimerization and MPL complex formation.
- Zinc chelation disrupted CALRdel52-MPL complexes and preferentially eradicated CALRdel52-mutant cells.
Conclusions:
- Zinc acts as a crucial cofactor for CALRdel52 oncogenic activity by facilitating multimerization and MPL interaction.
- Perturbing intracellular zinc levels presents a novel therapeutic approach for CALR-mutant MPNs.
