V-MYB OF E26 LEUKEMIA-VIRUS UP-REGULATES BCL-2 AND SUPPRESSES APOPTOSIS IN MYELOID CELLS

Many oncogenes have been shown to be deregulated transcription factors , yet direct target genes mediating cell transformation remain elusive . Here we describe such a target for v-Myb by exploiting a temperature -sensitive mutant of the E26 avian leukemia virus encoding Myb-Ets. My eloblasts transformed by the mutant differentiate into macrophages or die by apoptosis when shifted to the nonpermissive temperature as a re sult of inactivation of v-Myb. During this process mRNA of the antiapo ptotic oncoprotein Bcl-2 is down-regulated with kinetics similar to th ose of Mim-1, a differentiation-related protein whose expression is di rectly regulated by Myb. Forced expression of bcl-2 rescues the cells from apoptosis, without preventing either their withdrawal from the ce ll cycle or their differentiation. v-Myb appears to act directly on th e bcl-2 gene, because a bcl-2 promoter-driven reporter is activated by Myb-Ets and v-Myb-VP16 and requires intact Myb binding sites within t he promoter. Surprisingly, inactivation of v-Myb in multipotent progen itors transformed by E26 virus does not induce apoptosis, indicating t hat bcl-2 regulation by the oncoprotein is required for the transforma tion of some cell types but not others.