Transformation of myeloid cells by the retroviral oncogene v-myb is thought to be caused by deregulated expression of specific cellular genes that act as targets of v-Myb in myeloid cells. Recently, we have identified the chicken tom-1 gene as a direct target for v-Myb. tom-1 has two promoters, only one of which (the tom-IA promoter) is activated by v-Myb. Here, we show that v-Myb activates the tom-IA promoter by cooperating with Ets-2, a member of the Ets transcription factor family. Interestingly, we find that the ability of v-Myb to cooperate with Ets proteins differs from that of its non-oncogenic cellular counterpart c-Myb. c-Myb cooperates with Ets-l and Ets-2, whereas v-Myb only cooperates with Ets-2. Truncation of the N-terminus of c-Myb, which is known to activate the oncogenic potential of c-Myb, specifically abrogates the ability of the protein to cooperate with Ets-l. Our findings, therefore, reveal a novel function for the N-terminus of c-Myb and raise the possibility that oncogenic activation of c-Myb is linked to the loss of cooperation between Myb and c-Ets-1. (C) 1999 Elsevier Science B.V. All rights reserved.