The Nuclear Organization and Post-Translational Control in Pathophysiologyteam , headed by Pr Hugues de Thé and Dr Valérie Lallemand-Breitenbach, based at Collège de France (CIRB) and Hôpital Saint-Louis, studies the biology of PML nuclear bodies. These cellular compartments are formed by the eponymous protein (PML) and are involved in the regulation of numerous biological functions, including anti-cancer functions such as the induction of cell death. The team is interested in an aggressive form of blood cancer called acute promyelocytic leukemia (APL), in which the disorganization of PML bodies contributes to the pathogenesis of the disease. The team's work had shown that arsenic cures almost all patients through its ability to bind to a PML domain and trigger degradation of the fusion protein responsible for the disease.
In a study published on September1 2023 in the journal Cancer Discovery, scientists from Collège de France, Inserm and CNRS, in collaboration with the team of Prof. Hua Naranmandura and Prof. Zhou from Zhejiang University in China, investigated the mechanisms by which these PML nuclear bodies are formed, and how they are regulated by arsenic. They discovered that a small part of the protein, called the B2 domain, plays a central role in this process. After elucidating the 3D structure of this B2 domain, they demonstrated that it has the ability to form trimers. Arsenic binds to the B2 box of PML on a trio of cysteine residues normally involved in the detection of oxidative stress. In PML, arsenic succeeds in forcing the formation of PML nuclear bodies by binding to these three cysteines and restoring a proliferation and survival checkpoint. This work thus explains, at the molecular level, the action of arsenic in this disease.
Illustration : PML nuclear bodies visualized by confocal microscopy. In the image, the PML protein is marked in green and the nucleus in blue.
