Abstract

C/EBPα is a key transcription factor involved in myeloid differentiation and frequently mutated or deregulated in human acute myeloid leukemias (AML) as well as in blast crisis of chronic myelogenous leukemia (CML). Disruption of its function contributes to the differentiation block observed in these diseases and thus to leukemogenesis. Here, we have identified a conserved region in the C/EBPα promoter that is important for activation of C/EBPα transcription in myeloid cells and narrowed it down to a conserved site of approximately 25 bp that contains a consensus binding site for ZFP143, a seven-zinc finger transcription factor. In gel retardation assays, this region bound a factor of approximately 100 kDa that we biochemically purified and identified by mass spectrometry as being indeed ZFP143. In vivo binding of ZFP143 to its bona fide binding site in the C/EBPα promoter was also detected by chromatin immunoprecipitation assays. We are now studying the in vivo effect of ZFP143 on C/EBPα transcription in mice that carry an inducible gene trap in the ZFP143 locus. While mice homozygous for the active gene trap - that prevents ZFP143 transcription - die at an early embryonic stage, preliminary data from heterozygous mice shows indeed a reduction of C/EBPα mRNA levels, suggesting a role for ZFP143 in C/EBPα transcription activation. Ongoing experiments aim at selectively inactivating ZFP143 in the hematopoietic system using the Mx1-Cre / loxP system.

Author notes

Disclosure: No relevant conflicts of interest to declare.