C/EBPα and C/EBPα oncoproteins regulate nfkb1 and displace histone deacetylases from NF-κB p50 homodimers to induce NF-κB target genes

Mutated CEBPA defines a subgroup of acute myeloid leukemia (AML). We have previously shown that C/EBP alpha or its AML mutants synergize with NF-kappa B p50 to activate antiapoptotic genes, including BCL2 and FLIP. Furthermore, p50 binds and activates the CEBPA gene in myeloid cells. We now report that C/EBP alpha or C/EBP alpha leucine zipper AML mutants bind in vivo to the nfkb1 (p50) promoter and induce its expression even in the presence of cycloheximide. Induction of p50 by C/EBP alpha depends on 2 conserved kappa B sites in the nfkb1 promoter. C/EBP alpha did not induce p65 expression. Thus, C/EBP alpha and p50 reciprocally regulate each other's expression, establishing a positive feedback relationship. Although p50 homodimers inhibit transcription, C/EBP alpha and p50 synergistically activate antiapoptotic genes. ChIP analysis showed that C/EBP alpha diminishes the occupation of histone deacetylase 1 (HDAC1) or HDAC3 on the endogenous FLIP promoter but not in mice lacking p50. Coimmunoprecipitation confirmed that C/EBP alpha, its AML variants, or C/EBP beta disrupt interaction between p50 and HDACs dependent on the C/EBP basic region. These findings suggest that C/EBPs displace HDACs from p50 homodimers bound to antiapoptotic genes, contributing to NF-kappa B dysregulation in leukemia, and that the C/EBP alpha:p50 complex is a potential therapeutic target. (Blood. 2011;117(15):4085-4094)