title: Therapy-induced PML/RARA proteolysis and acute promyelocytic leukemia cure.
abstract: Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) chromosomal translocation that yields the PML/RARA fusion gene. Clinically, besides chemotherapy, two drugs induce clinical remissions: retinoic acid (RA) and arsenic trioxide (As). Both agents directly target PML/RARA-mediated transcriptional repression and protein stability, inducing to various extent promyelocyte differentiation and clinical remission of APL patients. RA targets the RARA moiety of the fusion, whereas arsenic targets its PML part. PML/RARA expression in the mouse is sufficient to initiate APL. The RA-As association, which synergizes for PML/RARA degradation but not for differentiation, rapidly clears leukemia initiating cells (LIC), resulting in APL eradication in murine APL models, but also in several APL clinical trials. Cyclic AMP triggered PML/RARA phosphorylation also enhances RA-induced APL regression, PML/RARA degradation, and LIC clearance, raising new options for therapy-resistant patients. Although differentiation has a major role in debulking of the tumor, PML/RARA degradation seems to be the primary basis for APL eradication by the RA-As association. Oncoprotein degradation could be a general therapeutic strategy that may be extended beyond APL.
authors.affiliation: Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Rihab
authors.initials: R
authors.lastname: Nasr
authors.forename: Valérie
authors.initials: V
authors.lastname: Lallemand-Breitenbach
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Guillemin
authors.forename: Hugues
authors.initials: H
authors.lastname: de Thé
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D004357:Drug Synergism; D006801:Humans; D007942:Leukemia, Experimental / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*
chemical_list: D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein