The eukaryotic translation initiation factor eIF4E is a direct transcriptional target of NF-κB and is aberrantly regulated in acute myeloid leukemia

The eukaryotic translation initiation factor eIF4E is a potent oncogene elevated in many cancers, including the M4 and M5 subtypes of acute myeloid leukemia (AML). Although eIF4E RNA levels are elevated 3- to 10-fold in M4/M5 AML, the molecular underpinnings of this dysregulation were unknown. Here, we demonstrate that EIF4E is a direct transcriptional target of nuclear factor kappa-lightchain- enhancer of activated B cells (NF-kappa B) that is dysregulated preferentially in M4 and M5 AML. In primary hematopoietic cells and in cell lines, eIF4E levels are induced by NF-kappa B activating stimuli. Pharmacological or genetic inhibition of NF-kappa B represses this activation. The endogenous human EIF4E promoter recruits p65 and cRel to evolutionarily conserved kB sites in vitro and in vivo following NF-kappa B activation. Transcriptional activation is demonstrated by recruitment of p300 to the kB sites and phosphorylated Pol II to the coding region. In primary AML specimens, generally we observe that substantially more NF-kappa B complexes associate with eIF4E promoter elements in M4 and M5 AML specimens examined than in other subtypes or unstimulated normal primary hematopoietic cells. Consistently, genetic inhibition of NF-kappa B abrogates eIF4E RNA levels in this same population. These findings provide novel insights into the transcriptional control of eIF4E and a novel molecular basis for its dysregulation in at least a subset of M4/M5 AML specimens.