期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2013
卷号：110
期号：33
页码：13522-13527
DOI：10.1073/pnas.1310067110
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 (PLZF-RAR) and RAR-PLZF, both of which participate in leukemia development. Here we provide evidence that the activity of CCAAT/enhancer binding protein (C/EBP), 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-PLZF inhibits myeloid cell differentiation through interactions with C/EBP tethered to DNA, using ChIP and DNA capture assays. Furthermore, RAR-PLZF recruits HDAC1 and causes histone H3 deacetylation at C/EBP target loci, thereby decreasing the expression of C/EBP target genes. In line with these results, HDAC inhibitors restore in part C/EBP target gene expression. These findings provide molecular evidence for a mechanism through which RAR-PLZF acts as a modifier oncogene that subverts differentiation in the granulocytic lineage by associating with C/EBP and inhibiting its activity.
