The Myb gene family was first discovered because the v-Myb oncogene of the avian myeloblastosis virus (AMV) causes a rapidly fatal leukemia in chickens. The v-Myb protein is a doubly truncated and mutated version of the normal c-Myb protein. The c-Myb proto-oncogene has also been activated by retroviral insertional mutagenesis in avian B lymphoid and murine myeloid malignancies. The common theme of these activation events is the truncation of the amino and/or carboxyl termini of c-Myb. The long-term goal of this research project is to understand in detail the molecular mechanisms by which cellular Myb proteins regulate normal and malignant hematopoiesis. Previous studies have suggested that the carboxyl terminus of c-Myb can negatively regulate the central transcriptional activation domain of c-Myb and/or inhibit DNA-binding by the amino terminus of c-Myb. However, negative regulation by the carboxyl terminus of c-Myb does not occur in budding yeast. This result implies that this regulation requires additional protein(s) present in animal cells but not in yeast. In this regard, we have recently shown that the vertebrate BS69 protein can bind to the carboxy-terminal regulatory region of c-Myb and thereby inhibit transcriptional activation. BS69 is of particular interest because it was initially identified as a transcriptional inhibitor that binds directly to the adenovirus E1A-binding protein. Amino terminal truncation of c-Myb can also result in oncogenic activation. Previous studies have shown that deletion of the first of the three Myb repeats (as occurs in v-Myb) strongly activates c-Myb for the transformation of myelomonocytic cells in culture. Recently others have reported that deletion of only 20 amino-terminal residues of c-Myb occurs following retroviral insertional mutagenesis in chicken B cell lymphomas. Despite retaining all three Myb repeats, such a deleted protein causes lymphomas, carcinomas, and sarcomas, but not myeloid malignancies in chickens. We propose to develop a cell culture assay for transformation by this activated form of c-Myb and to investigate its biochemical and biological properties.
