c-myb transactivates the human cyclin A1 promoter and induces cyclin A1 gene expression

Cyclin Al differs from other cyclins in its highly restricted expression pattern. Besides its expression during spermatogenesis, cyclin Al is also expressed in hematopoietic progenitor cells and in acute myeloid leukemia. We investigated mechanisms that might contribute to cyclin Al expression in hematopoietic cells, Comparison of cyclin Al and cyclin A promoter activity in adherent and myeloid leukemia cell lines showed that the cyclin Al promoter is preferentially active in myeloid cell lines. This preferential activity was present in a small, 335-bp cyclin Al promoter fragment that contained several potential c-myb binding sites. Coexpression of a c-myb expression vector with the cyclin Al promoter constructs significantly increased the reporter activity in adherent CV-1 as well as in myeloid U937 cells. Gel-shift assays demonstrated that c-myb could bind to the cyclin Al promoter at a binding site located near the transcription start site, Site-directed mutagenesis of this site decreased promoter transactivation by 50% in both KCL22 cells that express high levels of c-myb and in CV-1 cells that were transfected with c-myb, In addition, transfection of primary human embryonic fibroblasts with a c-myb expression vector led to induction of the endogenous cyclin Al gene. Taken together, c-myb can directly transactivate the promoter of cyclin Al, and c-myb might be involved in the high-level expression of cyclin Al observed in acute myeloid leukemia. These findings suggest that c-myb induces hematopoiesis-specific mechanisms of cell cycle regulation. (C) 1999 by The American Society of Hematology.