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Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13522-7. doi: 10.1073/pnas.1310067110. Epub 2013 Jul 29.

RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells.

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  • 1Institute of Research in Immunology and Cancer (IRIC), Molecular Biology Program, and Department of Pharmacology, University of Montreal, Montreal, QC, Canada H3C 3J7.

Abstract

In acute promyelocytic leukemia, granulocytic differentiation is arrested at the promyelocyte stage. The variant t(11;17) translocation produces two fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF-RARα) and RARα-PLZF, both of which participate in leukemia development. Here we provide evidence that the activity of CCAAT/enhancer binding protein α (C/EBPα), a master regulator of granulocytic differentiation, is severely impaired in leukemic promyelocytes with the t(11;17) translocation compared with those associated with the t(15;17) translocation. We show that RARα-PLZF inhibits myeloid cell differentiation through interactions with C/EBPα tethered to DNA, using ChIP and DNA capture assays. Furthermore, RARα-PLZF recruits HDAC1 and causes histone H3 deacetylation at C/EBPα target loci, thereby decreasing the expression of C/EBPα target genes. In line with these results, HDAC inhibitors restore in part C/EBPα target gene expression. These findings provide molecular evidence for a mechanism through which RARα-PLZF acts as a modifier oncogene that subverts differentiation in the granulocytic lineage by associating with C/EBPα and inhibiting its activity.

KEYWORDS:

APL; granulocyte differentiation; histone modification; protein interaction; transcription inhibition

PMID:
23898169
[PubMed - indexed for MEDLINE]
PMCID:
PMC3746863
Free PMC Article
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