Oncogenes in murine acute myeloid leukemia

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In a murine model for myeloid leukemogenesis, the c-myb gene is a primary target of insertional. A recent focus of the laboratory has been to clarify the biological roles of c-Myb in leukemia progression and identify specific genes that are regulated by c-Myb at the transcriptional level. We have found that c-Myb transforms cells through multiple mechanisms including: 1) positive regulation of cell growth by both directly transactivating a cell proliferation gene(s) such as c-myc as well as preventing upregulation in monocytic cells of tumor suppressor(s) 2) inhibition of apoptosis by transactivating Bcl-2. The way in which c-Myb affects tumor suppressor expression is the subject of our most recent research on Myb transformation. Interesting, we have found that, in c-Myb transformed cells and in differentiating myeloid cells constitutively expressing c-Myb, the tumor suppressor p15Ink4b, a cdk inhibitor, is specifically prevented from being turned on. This is a characteristic of cells constitutively expressing c-Myb, but not those constitutively expressing B-Myb or c-Myc. In normal cells this tumor suppressor is upregulated during differentiation and associated with growth arrest of myeloid cells. We confirmed that in our leukemias in which the c-myb is activated by insertional mutagenesis the p15Ink4b gene is not methylated as it is in a great majority of human AMLs and lymphomas of human and murine origin. Our recent studies contribute to the idea that c-Myb has several roles as a transcription factor that individually can enhance leukemia cell outgrowth.