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

Fabien Guidez, Sarah Parks, Henna Wong, Jelena V. Jovanovic, Ashley Mays, Amanda F. Gilkes, Kenneth I. Mills, Marie Claude Guillemin, Robin M. Hobbs, Pier Paolo Pandolfi, Hugues De Thé, Ellen Solomon, David Grimwade

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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.

Original languageEnglish
Pages (from-to)18694-18699
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number47
DOIs
Publication statusPublished - 20 Nov 2007
Externally publishedYes

Keywords

  • Chromatin
  • Remodelling

Cite this

Guidez, F., Parks, S., Wong, H., Jovanovic, J. V., Mays, A., Gilkes, A. F., Mills, K. I., Guillemin, M. C., Hobbs, R. M., Pandolfi, P. P., De Thé, H., Solomon, E., & Grimwade, D. (2007). RARα-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), 18694-18699. https://doi.org/10.1073/pnas.0704433104