c-myb and Mmll continue to be the focus of the laboratory since we have found that these two loci are important to the development of promonocytic leukemia. Both are targets of insertional mutagenesis by retroviruses in our animal model. Previous data from our laboratory has shown that the c-myb oncogene can be activated when the retrovirus integrates into the 5' end of the gene and causes constitutive mRNA expression by a mechanism referred to as promotor insertion. In vitro data suggest that the consequence of uncontrolled expression of this gene, which encodes a transcription factor, is the inhibition of growth arrest that occurs at end stages of myeloid cell differentiation. This past year our laboratory has been studying an alternative form of activation that occurs in others leukemia's when virus integrates into exon 9. This results in truncation of the c-Myb protein at its carboxylterminus (CT) and our evidence suggests that this is an oncogenic event because it causes the protein to be more resistant to proteolysis. It was determined that the half-life of CT-truncated Myb is significantly longer than that of wild-type c-Myb, allowing the protein to be expressed at inappropriate times. We also determined that c-Myb is normally degraded rapidly by the ubiquitin- 26S proteasome pathway, a system shown recently to be utilized for degradation of many short-lived regulatory proteins, including transcription factors. The Mmll locus was identified as a target of insertional mutagenesis in many leukemia's that lack integration within the c-myb locus. In preliminary experiments we cannot demonstrate that integration at this site effects transcription of c-myb. We are presently pursing this possibility, however, as well as looking for the presence of novel transcripts within the vicinity of Mmll.
