RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia.
Fiche publication
Date publication
novembre 2007
Journal
Proceedings of the National Academy of Sciences of the United States of America
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GUIDEZ Fabien
Tous les auteurs :
Guidez F, Parks S, Wong H, Jovanovic JV, Mays A, Gilkes AF, Mills KI, Guillemin MC, Hobbs RM, Pandolfi PP, de Thé H, Solomon E, Grimwade D
Lien Pubmed
Résumé
Leukemia-associated chimeric oncoproteins often act as transcriptional repressors, targeting promoters of master genes involved in hematopoiesis. We show that CRABPI (encoding cellular retinoic acid binding protein I) is a target of PLZF, which is fused to RARalpha by the t(11;17)(q23;q21) translocation associated with retinoic acid (RA)-resistant acute promyelocytic leukemia (APL). PLZF represses the CRABPI locus through propagation of chromatin condensation from a remote intronic binding element culminating in silencing of the promoter. Although the canonical, PLZF-RARalpha oncoprotein has no impact on PLZF-mediated repression, the reciprocal translocation product RARalpha-PLZF binds to this remote binding site, recruiting p300, inducing promoter hypomethylation and CRABPI gene up-regulation. In line with these observations, RA-resistant murine PLZF/RARalpha+RARalpha/PLZF APL blasts express much higher levels of CRABPI than standard RA-sensitive PML/RARalpha APL. RARalpha-PLZF confers RA resistance to a retinoid-sensitive acute myeloid leukemia (AML) cell line in a CRABPI-dependent fashion. This study supports an active role for PLZF and RARalpha-PLZF in leukemogenesis, identifies up-regulation of CRABPI as a mechanism contributing to retinoid resistance, and reveals the ability of the reciprocal fusion gene products to mediate distinct epigenetic effects contributing to the leukemic phenotype.
Mots clés
Base Sequence, Binding Sites, Cell Line, Chromatin, genetics, Chromosomes, Human, Pair 11, genetics, Chromosomes, Human, Pair 17, genetics, DNA Methylation, Disease Progression, Drug Resistance, Neoplasm, drug effects, Gene Expression Regulation, Neoplastic, Humans, Kruppel-Like Transcription Factors, metabolism, Leukemia, Promyelocytic, Acute, genetics, Molecular Sequence Data, Promyelocytic Leukemia Zinc Finger Protein, Receptors, Retinoic Acid, genetics, Retinoic Acid Receptor alpha, Retinoids, pharmacology, Up-Regulation
Référence
Proc Natl Acad Sci U S A. 2007 11 20;104(47):18694-9