Secreted Mutant Calreticulins Behaving as Cytokines
Researchers probed mutant calreticulins to determine whether they were secreted and behaved extracellularly as cytokines.
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Calreticulins (CALRs) that are mutated with a C-terminus + 1 frameshift are often associated with myeloproliferative neoplasms through thrombopoietin receptor (TpoR) activation, causing enhancement of the JAK2-STAT5 pathway.
However, the fate and other behaviors of these mutant calreticulins have remained unclear until they were examined in a study presented at the 60th American Society of Hematology (ASH) Annual Meeting in San Diego, California.
The researchers probed mutant CALR and TpoR interactions to determine whether mutant CALRs are secreted and can behave extracellularly as cytokines. Their assessments employed a variety of biochemical, functional, and cell imaging techniques, such as bioluminescence resonance energy transfer, transcriptional assays, flow cytometry, and confocal and immunogold electron microscopy, among other methods.
The research team observed a direct interaction between TpoR and mutant CALRs. No such interaction was apparent between TpoR and wild-type CALRs or between erythropoietin receptor (EpoR) and either tested form of CALR.
These mutant CALRs were also found to be secreted after being trafficked to the cell surface by cis-, medial-, and trans-Golgi. Evaluation of 113 patients with mutant CALRs demonstrated that the level of mutant CALR in plasma was associated with the CALR mutant allele burden (P <.001, with 113 patients).
Finally, the results showed that the mutant CALRs were able to behave as cytokines, enhancing activation of the JAK2-STAT5 pathway in cells displaying surface TpoR, but not cells displaying surface EpoR, and only with TpoRs with 1 or more immature N-linked sugar.
The authors concluded that mutant CALRs complex with and activate TpoR, are secreted, and behave as cytokines acting upon other cells. The researchers recommended development of immunotherapy approaches to exploit this system for treatment of myeloproliferative neoplasms.
Disclosures: Multiple authors declare affiliations with the pharmaceutical industry. For a full list of disclosures, please refer to the original study.
To read more of Hematology Advisor's coverage of the American Society of Hematology (ASH) 2018 meeting, please visit the conference page.
1. Pecquet C, Balligand T, Chachoua I, et al. Secreted mutant calreticulins as rogue cytokines trigger thrombopoietin receptor activation specifically in CALR mutated cells: perspectives for MPN therapy. Oral presentation at: 60th ASH Annual Meeting & Exposition. December 1-4, 2018; San Diego, CA.