Hugues de Thé has a dual medical and scientific background (see CV). He explores the relationships between gene transcription, nuclear architecture and cancer development. Following the discovery of a retinoic acid receptor and the first response element to this hormone during his thesis in Pierre Tiollais' laboratory at the Institut Pasteur, he made a key contribution to the characterization of PML/RARA, the gene at the origin of acute promyelocytic leukemia (APL).
He has since devoted himself entirely to understanding the action of PML/RARA, showing that it exerts dominant-negative effects on both transcriptional regulation and the organization of PML nuclear bodies. The drugs active in APL, arsenic and retinoic acid, both induce degradation of the PML/RARA protein, with arsenic targeting the PML part and retinoic acid the RARA part.
Using animal models of this leukemia, he was able to demonstrate that the induction of PML/RARA degradation by retinoic acid or arsenic is indeed at the origin of their clinical benefits, and that the combination of these two agents definitively cures the disease by a mechanism involving the reformation of PML bodies. Clinical trials directly inspired by his work have led to the definitive cure of almost all patients, making LAP the first example of leukemia cured by targeted treatments.
Using the LAP model as a starting point, he went on to provide original Spotlights on fundamental issues of cell biology, such as the assembly of PML nuclear bodies, and biochemistry, such as the sumoylation/ubiquitination/degradation coupling of proteins. His current work is aimed at elucidating the molecular mechanisms of response to anti-cancer treatments in other forms of leukemia. In particular, he is investigating the role of PML in therapeutic response to conventional agents, and the influence of retinoic acid on leukemias in which RARA is not involved. A presentation tracing the history of these discoveries, given at a recent conference at CSHL, is available online.
He currently works at Hôpital St Louis and Collège de France. His work is supported by the ERC, Institut National du Cancer, Fondation ARC and Ligue Nationale contre le Cancer.
