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: 6902685
• 负责人: DONG-ER ZHANG
• 金额: $ 37.59万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6902685
• 关键词: 3T3 cells; acute myelogenous leukemia; cAMP response element binding protein; carcinogenesis; cell differentiation; cell proliferation; chimeric proteins; chromosome translocation; gene expression; gene targeting; genetically modified animals; hematopoiesis; hematopoietic stem cells; laboratory mouse; leukemia; molecular oncology; neoplasm /cancer genetics; oncoproteins; polymerase chain reaction; sex chromosomes; transcription factor

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）是急性髓样白血病中最常见的遗传异常之一，在15％的情况下确定。 该转运产生融合蛋白AML1-Eto，其中包含AML1蛋白的N末端区域，包括Runt DNA结合结构域，几乎是C末端区域的整个ETO蛋白。 该建议检验了以下假设：t（8; 21）融合蛋白AML1-Eto需要其他突变的白血病发生，旨在鉴定与附加突变相关的分子途径。 对AML1敲除小鼠的研究表明，AML1在造血过程中起着至关重要的作用。 我们对AML1-Eto敲击小鼠的分析表明，在早期造血细胞承诺中，AML1-Eto主要阻断AML1功能。 此外，我们的数据表明AML1-Eto表达不足以引起白血病。 特定目标1中提出的研究将研究AML1-Eto对AML1-Eto的ES细胞对造血细胞承诺的影响，并将其撞入AML1基因座。 在特定目标2中提出的研究将研究性别染色体参与T（8; 21）相关的急性骨髓性白血病的发展，并使用基因工程小鼠。 特定目标3中提出的研究将研究与转基因小鼠中急性髓髓性白血病有关的与t（8; 21）发展相关的其他基因的突变。 我们已经建立了具有诱导型或髓样特异性表达的动物模型。 提出的实验将解决有关正常血细胞分化至关重要的因素以及T（8; 21）与白血病的发展有关的基本问题。