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) 并将 AML1 基因并置在 21 号染色体上 与 8 号染色体上的 ETO 基因结合，生成 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和作用机制 造血祖细胞的作用以及 AML1/ETO 对造血祖细胞的重要性 具有t(8;21)的白血病细胞的特定表型。 为了完成 对于这些目标，我建议 1）定义转录效应 AML1/ETO，即其结合DNA并影响DNA表达的能力 影响正常造血细胞生长和发育的基因，2) 定义 AML1/ETO 转化 NIH 3T3 细胞的能力，并确定 通过逆转录病毒基因导入AML1/ETO融合基因的效果 转移技术，对正常细胞的生长和分化 造血祖细胞，以及 3) 确定 AML1/ETO 对造血祖细胞的重要性 含有髓系白血病的t(8;21)的生长和分化 通过使用反义 DNA 抑制 AML1/ETO 蛋白表达来抑制细胞系 和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和使用融合TF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.