期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 33, 页码 13522-13527出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1310067110
关键词
APL; granulocyte differentiation; transcription inhibition; histone modification; protein interaction
资金
- Leukemia Lymphoma Society of Canada (LLSC)
- Cancer Research Society, Inc.
- Canadian Institutes for Health Research
- Fonds de Recherche du Quebec-Sante (FRQS)
- Cole Foundation
- LLSC
- Swiss National Foundation
- FRQS
- Canada Foundation for Innovation
- Networks of Centres of Excellence through the Centre of Excellence for Commercialization and Research program
- Cancer network of the FRQS
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 alpha (PLZF-RAR alpha) and RAR alpha-PLZF, both of which participate in leukemia development. Here we provide evidence that the activity of CCAAT/enhancer binding protein alpha (C/EBP alpha), 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 RAR alpha-PLZF inhibits myeloid cell differentiation through interactions with C/EBP alpha tethered to DNA, using ChIP and DNA capture assays. Furthermore, RAR alpha-PLZF recruits HDAC1 and causes histone H3 deacetylation at C/EBP alpha target loci, thereby decreasing the expression of C/EBP alpha target genes. In line with these results, HDAC inhibitors restore in part C/EBP alpha target gene expression. These findings provide molecular evidence for a mechanism through which RAR alpha-PLZF acts as a modifier oncogene that subverts differentiation in the granulocytic lineage by associating with C/EBP alpha and inhibiting its activity.
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