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Translocation of chromosomes 8 and 21 [t(8;21)] leads to fusion of the AML1 and ETO genes (AML1-ETO) and is associated with about 12 percent of acute myeloid leukemia (AML) cases. AML1 is a DNA-binding protein that regulates many aspects of hematopoietic transcription to impart a differentiation signal on the cell, while ETO generally acts as a transcriptional repressor with the ability to bind transcriptional corepressors. The AML-ETO fusion retains the ability to bind DNA and has been shown to inappropriately recruit transcriptional repressors (through ETO). The inappropriate transcriptional response elicited by the fusion protein impairs differentiation, implicating AML1-ETO as a key participant in the aberrant regulation of hematopoiesis that often leads to AML.
One goal of our work is to identify novel co-binding partners of AML1-ETO that could serve as potential targets for the treatment of t(8;21)-associated AML. We are also examining the functional domains of the AML1-ETO protein in a classic structure / function approach. Specifically, we aim to determine the critical domain(s) necessary for AML1-ETO mediated self-renewal in our human model system. Additionally, we are exploring several pathways to measure the effect of the AML1-ETO functional domains on leukemogenesis and maintenance of the phenotype associated with this leukemia. Ultimately, these studies may reveal novel targets that could be exploited to develop promising therapeutics for the treatment of AML.
We are testing AML1-ETO mutants for their ability to promote the long-term growth and self-renewal of human HSPC. This information will complement our approach of identifying those proteins that co-purify with the tagged AML1-ETO protein in the human CD34+ cells.
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