REGULATION OF GM-CSF GENE-TRANSCRIPTION BY CORE-BINDING FACTOR

GM-CSF gene activation in T cells is known to involve the transcriptio n factors nuclear factor-kappa B, AP-1, NFAT, and Sp1. Here we demonst rate that the human GM-CSF promoter and enhancer also encompass bindin g sites for core-binding factor (CBF). Significantly, the CBF sites ar e in each case contained within the minimum essential core regions req uired for inducible activation of transcription, Furthermore, these co re regions of the enhancer and promoter each encompass closely linked binding sites for CBF, AP-1, and NFATp. The GM-CSF promoter CBF site T GTGGTCA is located 51 bp upstream of the transcription start site and also overlaps a YY-1 binding site. A 2-bp mutation within the CBF site resulted in a 2-3-fold decrease in the activities of both a 69-bp pro ximal promoter fragment and a 627-bp full-length promoter fragment. St epwise deletions into the proximal promoter also revealed that the CBF site, but not the YY-1 site, was required for efficient induction of transcriptional activation. The AML1 and CBF beta genes that encode CB F each have the ability to influence cell growth and differentiation a nd have been implicated as proto-oncogenes in acute myeloid leukemia. This study adds GM-CSF to a growing list of cytokines and receptors th at are regulated by CBF and which control the growth, differentiation, and activation of hemopoietic cells. The GM-CSF locus may represent o ne of several target genes that are dysregulated in acute myeloid leuk emia.