AML1/ETO FUSION PROTEIN AND LEUKEMOGENESIS

t（8;21）是急性白血病中最常见的染色体畸变之一。 骨髓性白血病（AML），并在21号染色体上并置AML 1基因 与8号染色体上的ETO基因，以产生AML 1/ETO嵌合体 转录因子（TF）。 本项目的目标是确定 AML 1/ETO在肿瘤转化中的作用及机制 AML 1/ETO对造血祖细胞的重要性 t（8;21）白血病细胞的特异性表型。 完成 这些目标，我建议1）定义转录的影响， AML 1/ETO，即其结合DNA并影响 影响正常造血细胞生长和发育的基因，2） 定义AML 1/ETO转化NIH 3 T3细胞的能力，并确定 逆转录病毒基因导入AML 1/ETO融合基因的效果 转移技术，对正常的生长和分化 造血祖细胞，和3）确定AML 1/ETO的重要性， 含t（8;21）的髓系白血病的生长和分化 用反义DNA抑制AML 1/ETO蛋白表达的细胞系 RNA策略 该项目的结果将提供深入了解 人类白血病的发病机制及融合转铁蛋白应用的可行性 作为开发基于分子的治疗方法的靶点。

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.