| 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 RARα 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-RARα oncoprotein has no impact on PLZF-mediated repression, the reciprocal translocation product RARα-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/RARα+RARα/PLZF APL blasts express much higher levels of CRABPI than standard RA-sensitive PML/RARα APL. RARα-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 RARα-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. © 2007 by The National Academy of Sciences of the USA. |
| Keywords: |
controlled study; unclassified drug; oncoprotein; gene translocation; human cell; promoter region; genetics; disease course; nonhuman; molecular genetics; protein analysis; animal cell; metabolism; protein targeting; cell line; protein binding; gene locus; drug effect; drug resistance; pathology; drug resistance, neoplasm; dna methylation; gene expression regulation; leukemia, promyelocytic, acute; gene expression regulation, neoplastic; molecular sequence data; chromatin; disease progression; nucleotide sequence; gene repression; tumor protein; promyelocytic leukemia; kruppel like factor; kruppel-like transcription factors; murinae; base sequence; binding site; gene control; binding sites; upregulation; gene silencing; up-regulation; chromosome 11; chromosomes, human, pair 11; retinoic acid; retinoid; chromosome 17; chromosomes, human, pair 17; retinoic acid receptor alpha; retinoic acid receptor; retinoids; protein p300; chromatin condensation; receptors, retinoic acid; remodelling; protein crabp1; protein raralpha plzf; retinoic acid binding protein i, cellular; zbtb16 protein, human
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