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

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.

• Authors: Nathalie Girard, Mathieu Tremblay, Magali Humbert, Benoît Grondin, André Haman, Jean Labrecque, Bing Chen, Zhu Chen, Sai-Juan Chen, Trang Hoang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 33 Pg. 13522-7 (Aug 13 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23898169 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCAAT-Enhancer-Binding Protein-alpha
• Histones
• Kruppel-Like Transcription Factors
• Oncogene Proteins, Fusion
• Promyelocytic Leukemia Zinc Finger Protein
• RARA protein, human
• Receptors, Retinoic Acid
• Retinoic Acid Receptor alpha
• ZBTB16 protein, human
• Histone Deacetylase 1

Topics

• Blotting, Northern
• Blotting, Western
• CCAAT-Enhancer-Binding Protein-alpha (metabolism)
• Cell Differentiation (physiology)
• Cell Line
• Chromatin Immunoprecipitation
• Electrophoretic Mobility Shift Assay
• Gene Transfer Techniques
• Granulocyte Precursor Cells
• Granulocytes (physiology)
• Histone Deacetylase 1 (metabolism)
• Histones (metabolism)
• Humans
• Immunoprecipitation
• Kruppel-Like Transcription Factors (metabolism)
• Leukemia, Promyelocytic, Acute (genetics, metabolism)
• Oncogene Proteins, Fusion (metabolism)
• Promyelocytic Leukemia Zinc Finger Protein
• Receptors, Retinoic Acid (metabolism)
• Retinoic Acid Receptor alpha
• Translocation, Genetic (genetics)