A Chaperone Turned into an Oncoprotein: The Case of Calreticulin Mutants as Rogue Chaperones and Rogue Cytokines in Blood Cancer
The seminar will be followed by tea and coffee in the Combination Room
Myeloproliferative neoplasms are a group of blood cancers where acquired mutations by hematopoietic stem cells lead to excessive clonal proliferation of myeloid progenitors. While the most prevalent mutation is the JAK2 V617F activating mutation, recently 25-30% patients with MPNs were found to harbour acquired mutations in calreticulin (CALR). The mutations are deletions and insertions in the last exon of CALR leading to a +1 frameshift that generates a novel 40 aminoacid residue tail that contains positively charged residues and Methionine. We showed that the mutant CALR proteins gain affinity for the extracellular domain of one cytokine receptor in the cytokine receptor superfamily, namely the thrombopoietin receptor (TpoR, c-MPL). Using structural and biochemical approaches we mapped the direct interaction sites between mutant CALR and TpoR. These include both the classic lectin-sugar interactions known for wild type CALR, but also a specific interaction between the novel tail of mutant CALR that forms a dimeric coiled coil that binds negatively charged patches on one segment of TpoR. This results in permanent dimerization and activation of TpoR. Mutant CALRs act as rogue chaperones for TpoR, in that the complex is transported to the cell-surface where TpoR signals pathologically. Moreover, mutant CALRs act as rogue cytokines as they are secreted by cells belonging to the MPN clone that do not express TpoR and act on cells that already express endogenous mutant CALR by oligomerizing with it and binding TpoR with immature sugars at their surface. We provide evidence that explains why among thousands of N-glycosylated client proteins, mutant CALRs specifically form complexes and dimerize TpoR in a conformation productive to stimulate stem cells and megakaryocytic progenitors to establish myeloid cancers. Finally, given that cell-surface localization of the complex mutant CALR-TpoR is required for oncogenicity, several antibodies are entering clinical trials for blocking the clone proliferation or inducing specific killing of the mutant CALR clone.
Date: 26 June 2023, 13:00 (Monday, 10th week, Trinity 2023)
Venue: Sir William Dunn School of Pathology, South Parks Road OX1 3RE
Venue Details: EPA Seminar Room
Speaker: Stefan N. Constantinescu (Professor, Université catholique de Louvain, de Duve Institute / Member Ludwig Institute for Cancer Research, Brussels and Oxford / Professor of Cancer Signalling, Nuffield Department of Medicine, University of Oxford, Oxford, UK)
Organising department: Sir William Dunn School of Pathology
Organiser: Jo Peel (University of Oxford, Sir William Dunn School of Pathology)
Host: Professor Matthew Freeman (Sir William Dunn School of Pathology, University of Oxford)
Part of: Dunn School of Pathology Research Seminars
Booking required?: Not required
Audience: Members of the University only
Editor: Jo Peel