Elucidating how mutations in calreticulin induce blood cancer
Since 2000, Stefan Constantinescu's research team has been mapping the molecular basis of myeloproliferative neoplasms, a group of blood cancers associated with complications such as thrombosis that progress to leukaemia and become more frequent with age.
In 2005 and 2006, the team was involved in the discovery of two mutations that induce excessive proliferation of the cells that produce blood components. The first concerns a family of cell signalling molecules (JAK), the second concerns the TpoR protein (a receptor for thrombopoietin, a hormone that stimulates the formation of blood platelets). These findings have put the pharmaceutical industry on the trail of developing potential treatments that aim to block the JAK2 protein. Unfortunately, the JAK2 protein is common to many receptors and blocking it causes serious complications without curing the disease.
In 2013, the group discovered that a mutation in another protein, calreticulin, is involved in the majority of JAK2-negative myeloproliferative neoplasms. Stefan Constantinescu's team then discovered that the mutated calreticulin acts by binding and activating TpoR in an uncontrolled manner.
In an article published in Blood (2022), Christian Pecquet and Nicolas Papadopoulos, in collaboration with the Cliniques Universitaires Saint-Luc and Violaine Havelange, showed that the mutated calreticulin is present in the blood and only activates cells that carry the mutation. In addition, the protein is stable in the blood thanks to the presence of another protein, TFRC, which acts as a shield against enzymes that could degrade it.
The most recent publication (2023), in Nature Communications, provides the answer to a question that has puzzled scientists: why does mutated calreticulin bind to the thrombopoietin receptor and not to other proteins? Thanks to the extremely precise mapping he was able to establish of the binding between the mutated calreticulin and the TpoR receptor, Nicolas Papadopoulos was able to determine the exact location where small molecules would have to be placed to dissociate or block the complex, thereby providing a picture of the receptor for the first time.
How will these successive discoveries change the lives of patients with myeloproliferative neoplasms? First of all, it should be remembered that there is currently no drug to treat this disease. The pharmaceutical industry is trying to develop antibodies that could bind to the mutated calreticulin to block its pathological action. The problem is that, as they are present on the surface of cells but also in plasma, the doses of antibodies required would be high, with the risk of increasing side effects. The discovery published in Nature Communications opens up a new, more precise and promising avenue: attempting to develop a molecule that would break the bond between the mutated calreticulin and the receptor.
- Papadopoulos et al (2023) Nat Commun, 14 :1881
- Pecquet et al (2022) Blood 141, 917–929
Source : Press release UCLouvain