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PML, the unexpected effector of APL cure by retinoic acid or arsenic.

Pr Hugues DE THE
Chaire Collège de France, Université Paris Diderot, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France

lundi 26 juin 2017 - 11h00 - Auditorium, IGBMC
Invité(e) par Hinrich GRONEMEYER & Jean-Louis MANDEL

Acute promyelocytic leukemia, APL, is not only a model for precision medicine, but also the first example of a malignancy cured by targeted therapies. APL is driven by the promyelocytic leukemia (PML), retinoic acid receptor alpha (RARA) fusion, a potent oncoprotein that deregulates transcription and perturbs nuclear organization. Clinical studies had demonstrated that retinoic acid (ATRA) or arsenic trioxide (ATO) exert potent and selective anti-APL effects. Both drugs bind PML/RARA, arsenic to its PML moiety and retinoic acid to the RARA one. Either drugs initiate PML/RARA degradation, while also modulating the function of normal PML and RARA. The synergistic targeting of PML/RARA by ATRA/ATO results in APL cell differentiation, apoptosis and senescence. Studies performed in mouse models, have allowed an unprecedented understanding of the basis for therapy response in vivo. These studies provided the rationale for ATRA/ATO-based protocols, yielding up to 98% definitive cures, in the absence of any DNA-damaging chemotherapy and without major toxicities.

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