T(8;21) in Blood Cell Proliferation and Differentiation

T(8;21) 在血细胞增殖和分化中的作用

• 批准号: 7600700
• 负责人: DONG-ER ZHANG
• 金额: $ 6.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600700
• 关键词: AML1-ETO fusion protein; Acute Myelocytic Leukemia; Address; Animal Model; Blood Cells; C-terminal; Cell Differentiation process; Cell Proliferation; Cells; DNA Binding Domain; Data; Development; Genes; Genetically Engineered Mouse; Hematopoiesis; Hematopoietic; Knock-in Mouse; Knockout Mice; Molecular; Molecular Abnormality; Mutation; Myelogenous; N-terminal; Pathway interactions; Play; RUNX1 gene; Role; Sex Chromosomes; Testing; Transgenic Mice; acute myeloid leukemia 1 protein; embryonic stem cell; human CBFA2T1 protein; leukemia; leukemogenesis; research study; t(8; 21)(q22; q22)

DESCRIPTION (provided by applicant): The t(8;21) is one of the most common genetic abnormalities in acute myeloid leukemia, identified in 15% of all cases. This translocation generates the fusion protein, AML1-ETO, which contains the N-terminal region of the AML1 protein, including the runt DNA binding domain, and almost the entire ETO protein at the C terminal region. This proposal tests the hypothesis that the t(8;21) fusion protein AML1-ETO requires additional mutations for leukemogenesis and aims to identify molecular pathways associated with the additional mutation. Study of AML1 knockout mice demonstrates that AML1 plays a critical role during hematopoiesis. Our analysis with AML1-ETO knock-in mice shows that AML1-ETO dominantly blocks AML1 function during early hematopoietic cell commitment. Furthermore, our data suggest that AML1-ETO expression is not sufficient to cause leukemia. The studies proposed in Specific Aim #1 will investigate the effect of AML1-ETO on hematopoietic cell commitment using ES cells with AML1-ETO knocked into the AML1 locus. The studies proposed in Specific Aim #2 will study the involvement of sex chromosomes in the development of t(8;21) associated acute myeloid leukemia using genetically engineered mice. The studies proposed in Specific Aim #3 will investigate the abnormal expression or the mutation of additional genes associated with the development of t(8;21) involved acute myeloid leukemia in transgenic mice. We have established animal models with either inducible or myeloid specific expression of AML1-ETO. The experiments proposed will address fundamental questions about the factors critical for normal blood cell differentiation and how t(8;21) is related to the development of leukemia.

描述（由申请人提供）：t（8;21）是急性髓性白血病中最常见的遗传异常之一，在所有病例中发现15%。 该易位产生融合蛋白AML 1-ETO，其含有AML 1蛋白的N-末端区域，包括runt DNA结合结构域，以及在C末端区域的几乎整个ETO蛋白。 该提案检验了t（8;21）融合蛋白AML 1-ETO需要额外突变才能发生白血病的假设，并旨在鉴定与额外突变相关的分子途径。 对AML 1基因敲除小鼠的研究表明，AML 1在造血过程中起着关键作用。 我们对AML 1-ETO基因敲入小鼠的分析表明，AML 1-ETO在早期造血细胞定型过程中主要阻断AML 1功能。 此外，我们的数据表明，AML 1-ETO表达不足以导致白血病。 具体目标#1中提出的研究将使用AML 1-ETO敲入AML 1基因座的ES细胞研究AML 1-ETO对造血细胞定型的影响。 具体目标#2中提出的研究将使用基因工程小鼠研究性染色体在t（8;21）相关急性髓性白血病发展中的参与。 具体目标#3中提出的研究将调查与转基因小鼠中涉及t（8;21）的急性髓性白血病的发展相关的其他基因的异常表达或突变。 我们已经建立了诱导型或髓系特异性表达AML 1-ETO的动物模型。 这些实验将解决一些基本问题，如正常血细胞分化的关键因素，以及t（8;21）与白血病发展的关系。