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RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia



RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia



Proceedings of the National Academy of Sciences of the United States of America 104(47): 18694-9



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 RAR alpha by the t(11;17)(q23;q21) translocation associated with retinoic acid (RA)resistant acute promyelocytic leukemia (APL). PLZF represses the CRABP1 locus through propagation of chromatin condensation from a remote intronic binding element culminating in silencing of the promoter. Although the canonical, PLZF-RAR alpha oncoprotein has no impact on PLZF-mediated repression, the reciprocal translocation product RAR alpha-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/RAR alpha+RAR alpha/PLZF APL blasts express much higher levels of CRABPI than standard RA-sensitive PML/RAR alpha APL. RAR alpha-PLZF confers RA resistance to a retinoid-sensitive acute myeloid leukemia (AML) cell line in a CRABPI-clepen dent fashion. This study supports an active role for PLZF and RARa-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.

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Accession: 055333354

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PMID: 18000064

DOI: 10.1073/pnas.0704433104



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