1. RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia.
- Author
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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, and Grimwade D
- Subjects
- Base Sequence, Binding Sites, Cell Line, Chromatin genetics, DNA Methylation, Disease Progression, Drug Resistance, Neoplasm drug effects, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Promyelocytic, Acute pathology, Molecular Sequence Data, Promyelocytic Leukemia Zinc Finger Protein, Receptors, Retinoic Acid genetics, Retinoic Acid Receptor alpha, Retinoids pharmacology, Up-Regulation, Chromosomes, Human, Pair 11 genetics, Chromosomes, Human, Pair 17 genetics, Kruppel-Like Transcription Factors metabolism, Leukemia, Promyelocytic, Acute genetics, Leukemia, Promyelocytic, Acute metabolism, Receptors, Retinoic Acid metabolism
- 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.
- Published
- 2007
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