Three genes with different functions in transformation are regulated by c-Myb in myeloid cells

The proto-oncogene c-myb is constitutively expressed in murine leukemia vir us-induced (m) under bar yeloid leukemia (MML) due to the integration of vi rus at this locus. Our recent focus has been the determination of genes reg ulated by this transcription factor that may be involved in transformation. Data presented here, using conditional expression of Myb in myeloid cells, show that c-Myb directly transactivates the endogenous c-myc and Bcl-2 gen es, which explains at least in part how c-Myb regulates proliferation and s urvival. In addition, c-Myb prevents expression at the RNA level of the tum or suppressor INK4b gene. This gene encodes a cyclin-dependent kinase inhib itor, p15(INK4b), that is normally upregulated at the mRNA level during mye loid differentiation and promotes growth arrest. The MMLs are generally cha racterized as differentiated monocytic tumors and possess the phenotype tha t is normally associated with p15(INK4b) expression. c-Myb inhibits express ion of this gene, however, and therefore acts to promote a pathway which is abnormal in mature cells. This activity of c-Myb collaborates with its mai ntenance of c-myc expression to promote growth. (C) 2001 Academic Press.