Targeting mechanisms of pathogenic mutant calreticulin signaling via thrombopoietin receptor and JAK2 in myeloproliferative neoplasms.
cancer • cell signalling • chaperones
Stefan Constantinescu is professor at the Université catholique de Louvain. His work at the de Duve Institute is dedicated to myeloproliferative neoplasms (MPNs), a group of hematopoietic stem cell pathologies that lead to an excessive production of blood cells. Certain types of MPNs are caused by mutations in the calreticulin gene, a chaperone protein.
The first two years of this project made it possible to describe a novel oncogenic mechanism whereby the mutant calreticulin (mCALR) activates the thrombopoietin receptor (TpoR). The mCALR-TpoR complex is abnormally brought to, and maintained on, the cell surface, where it continuously activates the JAK-STAT intra-cellular signalling path, which leads to the proliferation of blood stem cells. This discovery is the first example of a chaperone protein being transformed into an oncogene via a change in its specificity. This gives it a damaging chaperone activity.
The next two years will make it possible to investigate the structural basis of the TpoR-mCALR interaction and attempt to inhibit this complex on the cell surface using small molecules and immunotherapy. They will also assess the effects of the secreted mCALR on patients, especially on blood stem cells.