c-Maf induces monocytic differentiation and apoptosis in bipotent myeloid progenitors

The transcriptional mechanisms that drive colony-forming unit granulocyte-m acrophage (CFU-GM) myeloid progenitors to differentiate into cells of eithe r the granulocytic or monocytic lineage are not fully understood. We have s hown that the c-Maf and c-Myb transcription factors physically interact in myeloid cells to form inhibitory complexes that hinder transactivation of c -Myb target genes through direct binding to Myb consensus sites. These comp lexes arise in a developmentally regulated pattern, peaking at the promyelo cyte stage, or in cell model systems, appearing soon after the induction of monocytic differentiation. We wished to determine if this developmentally related interaction is a consequence of myeloid differentiation or an intri nsic differentiating stimulus. Because the elevated Myb:Maf status seen in differentiating cells can be recapitulated by overexpression of c-Maf in my eloid cell lines, we inducibly expressed the c-Maf cDNA in 2 bipotent human myeloid progenitor cells. Elevated levels of c-Maf protein led to marked i ncreases in Myb:Maf complexes and the accumulation of monocyte/ macrophage cells, followed by eventual programmed cell death. Analysis of targets that could mediate these phenotypic changes indicated that c-Maf likely plays a key role in myeloid cell development through dual mechanisms; inhibition o f a select set of c-Myb regulated targets, such as Bcl-2 and CD13/APN, coup led with the activation of as yet undefined differentiation-promoting genes . (C) 1999 by The American Society of Hematology.