Elf, S, Abdelfattah, NS, Baral, AJ et al. (7 more authors) (2018) Defining the requirements for the pathogenic interaction between mutant calreticulin and MPL in MPN. Blood, 131 (7). pp. 782-786. ISSN 0006-4971
Abstract
Mutations in calreticulin (CALR) are phenotypic drivers in the pathogenesis of myeloproliferative neoplasms. Mechanistic studies have demonstrated that mutant CALR binds to the thrombopoietin receptor MPL, and that the positive electrostatic charge of the mutant CALR C terminus is required for mutant CALR-mediated activation of JAK-STAT signaling. Here we demonstrate that although binding between mutant CALR and MPL is required for mutant CALR to transform hematopoietic cells; binding alone is insufficient for cytokine independent growth. We further show that the threshold of positive charge in the mutant CALR C terminus influences both binding of mutant CALR to MPL and activation of MPL signaling. We find that mutant CALR binds to the extracellular domain of MPL and that 3 tyrosine residues within the intracellular domain of MPL are required to activate signaling. With respect to mutant CALR function, we show that its lectin-dependent function is required for binding to MPL and for cytokine independent growth, whereas its chaperone and polypeptide-binding functionalities are dispensable. Together, our findings provide additional insights into the mechanism of the pathogenic mutant CALR-MPL interaction in myeloproliferative neoplasms.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2017, American Society of Hematology. This research was originally published in Blood Online, 'Elf, S, Abdelfattah, NS, Baral, AJ et al (2017). Defining the requirements for the pathogenic interaction between mutant calreticulin and MPL in MPN. Blood.' Published December 29, 2017. DOI: https://doi.org/10.1182/blood-2017-08-800896 |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Funding Information: | Funder Grant number Academy of Medical Sciences Not Known Leuka Not Known |
Depositing User: | Symplectic Publications |
Date Deposited: | 09 Jan 2018 13:19 |
Last Modified: | 29 Dec 2018 01:38 |
Status: | Published |
Publisher: | American Society of Hematology |
Identification Number: | 10.1182/blood-2017-08-800896 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:125969 |