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 ? (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.