Recent results just published by WELBIO Investigator Stefan Constantinescu (UCLouvain) and his team in the journal Blood report a novel mechanism by which that a class of mutants in the chaperone calreticulin induce blood cancers denoted as myeloproliferative neoplasms (MPNs).
The work demonstrates that mutated calreticulins hijack intracellular processing and the traffic to the cell surface of one key protein named thrombopoietin receptor (TpoR). Mutated calreticulins form tight complexes with TpoR, translocating it to the Golgi and cell-surface in an immature state that normally is not competent for exit from the endoplasmic reticulum. By doing so, the mutant calreticulin proteins are able to permanently activate the TpoR leading to excess and clonal proliferation of blood progenitors and eventually to blood cancer.
While the complex is formed in the cell, full oncogenic transformation requires cell-surface localization. Mass spectrometry experiments showed that TpoR in the complex at the cell-surface retains immature sugars due to binding to mutated calreticulins. Biophysical, mutagenesis and protein folding experiments showed that the two proteins interact within a distance of less than 10 nm, and that binding to mutated calreticulins induce dimerization of TpoR in an active conformation. Strikingly, these mutated calreticulins also can restore cell surface localization of a traffic-deficient mutant of TpoR (TpoR R102P) that is responsible for congenital amegakaryocytic thrombocythemia, a very severe disease.due to absence of the function of TpoR.
Stefan Constantinescu and his team provide evidence that mutated calreticulins are delinquent (rogue) chaperones for their client protein TpoR, and that the oncogenic effects require exposure of the TpoR-mutated CALR on the cell-surface. This is the first example of a chaperone turned into oncogene due to change in specificity and rogue chaperone activity. These results open the path for developing therapies that target mutated calreticulins at the cell-surface.
Article references: Pecquet, C., Chachoua, I., Roy, A., Balligand, T., Vertenoeil, G., Leroy, E., … Constantinescu, S. N. (2019). Calreticulin mutants as oncogenic rogue chaperones for TpoR and traffic-defective pathogenic TpoR mutants. Blood. https://doi.org/10.1182/blood-2018-09-874578