This proposal is focused on understanding the role of the translocation- derived fusion protein, AML1-ETO in oncogenic transformation. AML1 encodes the DNA binding components of Core Binding Factor (CBF) which, as a complex, binds to various enhancer regions and regulates transcription of several genes involved in hematopoietic differentiation. These include the T-cell receptor genes, granulocyte-macrophage colony stimulating factor, and the stem cell factor receptor, c-kit. AML-1/CBF functions in a context-dependent manner with other adjacently bound enhancer proteins rather then through multimerized single binding sites. This larger protein complex then regulates transcription of target promoters. In addition, knock-out experiments have shown that the AML1/CBF complex is required for fetal liver hematopoiesis. ETO is a nuclear protein that is developmentally regulated and a homologue for the Drosophila nervy protein. The chimeric protein, AML-ETO, retains the AML1 DNA binding domain, heterodimerizes with CBF, and dominantly interferes with CBF- mediated transactivation by target enhancers in myeloid cells, as shown using transient expression assays. Moreover, AML-ETO """"""""knock-in"""""""" mice are embryonic lethal and have a similar phenotype to AML-1 knock out mice, confirming its effect as a dominant inhibitor of AML1 function. The hypothesis that leukemia is caused, in part, by the ability of AML-ETO to alter transcription by a repression of interference mechanism will be tested in this proposal.
| Davis, J N; Williams, B J; Herron, J T et al. (1999) ETO-2, a new member of the ETO-family of nuclear proteins. Oncogene 18:1375-83 |
