Hugues de Thé has a dual medical and scientific background. 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 the protein synthesized by this gene, showing that PML/RARA exerts dominant negative effects on both transcription regulation and the organization of PML nuclear bodies. He showed that the two drugs active in APL, arsenic and retinoic acid, both induce degradation of the PML/RARA protein, arsenic targeting its PML portion and retinoic acid its RARA portion.
Using animal models of this leukemia, he was able to demonstrate that 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 led to the definitive cure of almost all patients, making LAP the first example of leukemia cured by targeted treatments.
Based on the LAP model, he has shed new light on fundamental issues in cell biology, such as the assembly of PML nuclear bodies, and biochemistry, such as the sumoylation/ubiquitination/degradation 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 the therapeutic response to agents other than arsenic.
