title: RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia.
abstract: 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.
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, London SE1 9RT, United Kingdom.
authors.forename: Fabien
authors.initials: F
authors.lastname: Guidez
authors.forename: Sarah
authors.initials: S
authors.lastname: Parks
authors.forename: Henna
authors.initials: H
authors.lastname: Wong
authors.forename: Jelena V
authors.initials: JV
authors.lastname: Jovanovic
authors.forename: Ashley
authors.initials: A
authors.lastname: Mays
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Gilkes
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Mills
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Guillemin
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hobbs
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Hugues
authors.initials: H
authors.lastname: de Thé
authors.forename: Ellen
authors.initials: E
authors.lastname: Solomon
authors.forename: David
authors.initials: D
authors.lastname: Grimwade
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002843:Chromatin / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D019175:DNA Methylation; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D002843:Chromatin; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; C082927:retinoic acid binding protein I, cellular; C092037:ZBTB16 protein, human