Two modes of disruption of the protooncogene c-myb by viral insertional mutagenesis In mouse myeloid tumor cells are described. The first mode was found in six tumors in which a Moloney murine leukemia virus component had inserted in the same transcriptional orientation upstream of the 5'-most exon with v-myb homology (vEl). cDNA sequence data indicate the presence of a truncated c-myb mRNA that is initiated in the upstream 5' long terminal repeat of the integrated provirus and processed via a cryptic splice donor sequence in the gag region to the splice acceptor site in vEl of the c-myb gene, thus removing the remaining downstream viral and myb intronic sequences. Unlike most gag-onc transcripts, the gag and myb sequences in the hybrid transcript were not in the same reading frame. It is presumed that the gag sequence provides a cryptic translation initiation site for the novel amino-truncated c-myb protein. The second mode of disruption was by downstream virus insertion at the 3' side of the c-myb, which results in the synthesis of a small (-2 kilobase) myb transcript. The 5' long terminal repeat of the inserted provirus provides a TGA termination codon that results in the elimination of 240 normal c-myb amino acid residues from the carboxyl terminus of the tumor-specific myb protein. These results suggest that truncated myb proteins play a role in neoplastic transformation of myeloid cells. Avian myeloblastosis virus (AMV) is a replicationdefective retrovirus which induces myeloblastosis in vivo and transforms myelomonocytic cells in vitro (35). The viral genome contains a v-myb sequence that is homologous to the middle portion of the chicken protooncogene c-myb (1,16,22,52,58) and is thought to be essential for its oncogenic properties (11,59). Another avian leukemia virus (ALV), E26, also has been shown to contain most of the v-myb sequences and an additional nucleotide sequence derived from the c-ets protooncogene (27,41). While the target cells of AMV are of the myeloid lineage, cells of the myeloid as well as erythroid lineages are transformed by E26 (36, 37, 50). It appears that the myeloid leukemogenicity shared by AMV and E26 correlates with the common myb sequence. The p75 protein encoded by normal c-myb is 30 kilodaltons (kDa) larger than the p45 protein encoded by the AMVtransduced v-myb (23). Several lines of evidence indicate that a variety of alterations in protooncogenes can render them oncogenic (reviewed in reference 64). It is, however, currently unclear whether truncation of the c-myb protein is the abnormality responsible for the tumors induced by v-myb.The acute transforming retroviruses of mammalian and avian origin have led to the identification of nearly 20 cellular oncogenes. Retroviruses that lack oncogenes can induce a variety of tumors by insertional mutagenesis which affects both known c-onc genes and previously unidentified cellular genes (e.g., int loci) that are now implicated in tumorigenesis (reviewed in reference 3). Two modes of insertional mutagenesis which involve oncoge...