AML1/ETO FUSION PROTEIN AND LEUKEMOGENESIS

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The t(8;21) is one of the most common chromosomal aberrations in acute myelogenous leukemia (AML) and juxtaposes the AML1 gene on chromosome 21 with the ETO gene on chromosome 8, to generate the AML1/ETO chimeric transcription factor (TF). The goals of this project are to determine the role and mechanism of action of AML1/ETO in the neoplastic transformation of hematopoietic progenitor cells and the importance of AML1/ETO to the specific phenotype of leukemic cells with the t(8;21). To accomplish these goals, I propose to 1) Define the transcriptional effects of AML1/ETO, namely its ability to bind DNA and affect the expression of genes that influence normal hematopoietic cell growth and development, 2) Define the ability of AML1/ETO to transform NIH 3T3 cells, and determine the effect of introducing the AML1/ETO fusion gene, by retroviral gene transfer techniques, on the growth and differentiation of normal hematopoietic progenitors, and 3) Determine the importance of AML1/ETO to the growth and differentiation of a t(8;21) containing myeloid leukemia cell line by inhibiting AML1/ETO protein expression using antisense DNA and RNA strategies. The results of this project will provide insight into the pathogenesis of human leukemia and the feasibility of using fusion TFs as targets for developing molecularly based therapeutic approaches.