Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia.
Fiche publication
Date publication
avril 1998
Journal
Blood
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GUIDEZ Fabien
Tous les auteurs :
Guidez F, Ivins S, Zhu J, Söderström M, Waxman S, Zelent A
Lien Pubmed
Résumé
Typical acute promyelocytic leukemia (APL) is associated with expression of the PML-RARalpha fusion protein and responsiveness to treatment with all-trans retinoic acid (ATRA). A rare, but recurrent, APL has been described that does not respond to ATRA treatment and is associated with a variant chromosomal translocation and expression of the PLZF-RARalpha fusion protein. Both PML- and PLZF-RARalpha possess identical RAR sequences and inhibit ATRA-induced gene transcription as well as cell differentiation. We now show that the above-mentioned oncogenic fusion proteins interact with the nuclear receptor corepressor N-CoR and, in comparison with the wild-type RARalpha protein, their interactions display reduced sensitivities to ATRA. Although pharmacologic concentration of ATRA could still induce dissociation of N-CoR from PML-RARalpha, it had a very little effect on its association with the PLZF-RARalpha fusion protein. This ATRA-insensitive interaction between N-CoR and PLZF-RARalpha was mediated by the N-terminal PLZF moiety of the chimera. It appears that N-CoR/histone deacetylase corepressor complex interacts directly in an ATRA-insensitive manner with the BTB/POZ-domain of the wild-type PLZF protein and is required, at least in part, for its function as a transcriptional repressor. As the above-noted results predict, histone deacetylase inhibitors antagonize oncogenic activities of the PML-RARalpha fusion protein and partially relieve transcriptional repression by PLZF as well as inhibitory effect of PLZF-RARalpha on ATRA response. Taken together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARalpha-associated leukemias to ATRA.
Mots clés
Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 17, DNA-Binding Proteins, genetics, Drug Resistance, Neoplasm, genetics, Gene Expression Regulation, Neoplastic, drug effects, Humans, Kruppel-Like Transcription Factors, Leukemia, Promyelocytic, Acute, drug therapy, Neoplasm Proteins, genetics, Nuclear Proteins, genetics, Nuclear Receptor Co-Repressor 1, Oncogene Proteins, Fusion, genetics, Promyelocytic Leukemia Zinc Finger Protein, Protein Binding, Repressor Proteins, genetics, Transcription Factors, genetics, Translocation, Genetic, Tretinoin, pharmacology, Tumor Cells, Cultured, Zinc Fingers
Référence
Blood. 1998 04 15;91(8):2634-42