AML1/ETO FUSION PROTEIN AND LEUKEMOGENESIS

T(8；21)是急性髓系白血病最常见的染色体异常之一。 髓系白血病与21号染色体AML1基因并列 利用8号染色体上的ETO基因，产生AML1/ETO嵌合体 转录因子(TF)。该项目的目标是确定 AML1/ETO在肿瘤转化中的作用及机制 造血祖细胞的研究进展及AML1/ETO对人类免疫功能的影响 具有t(8；21)的白血病细胞的特殊表型。要完成 这些目标，我建议1)定义转录效应 AML1/ETO，即其与DNA结合的能力，并影响其表达 影响正常造血细胞生长发育的基因2) 确定AML1/ETO转化NIH 3T3细胞的能力，并确定 逆转录病毒基因导入AML1/ETO融合基因的作用 移植技术，对正常生长分化的影响 造血祖细胞；3)决定AML1/ETO的重要性 T(8；21)型髓系白血病细胞的生长和分化 反义DNA抑制AML1/ETO蛋白表达的细胞株 和RNA策略。该项目的结果将提供对 人类白血病的发病机制及融合转铁蛋白的可行性 作为开发基于分子的治疗方法的目标。

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.