CORE BINDING FACTOR IN LEUKEMOGENESIS--INV(16) AND T(8;21)

白血病发生中的核心结合因子--INV(16)和T(8;21)

• 批准号: 6102714
• 负责人: DAVID CLAXTON
• 金额: $ 16.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-07 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102714
• 关键词: acute myelogenous leukemia; carcinogenesis; cell cycle; cell differentiation; chimeric proteins; chromosome aberrations; fusion gene; gene expression; genetically modified animals; hematopoiesis; human tissue; laboratory mouse; neoplasm /cancer genetics; tissue /cell culture; transcription factor

The Inversion 16 (inv16) and t(8;21) chromosomal abnormalities are associated with a specific disease morphology and a relatively good prognosis in acute myelogenous leukemia. The genes encoded about each breakpoint have been cloned by the investigators as have the fusion cDNAs encoded by the chimeric genes. Core binding factor (CBF - formerly known as PEPB2), is a heterodimeric transcription factor formed by the alpha and beta subunit CBF gene products. The inv(16) causes a fusion of 5' coding sequences of CBFB (encoded at 16q22) to the MYH11 (a myosin heavy chain gene) 3' coding sequences (16p13). t(8;21) fuses AML1, encoding the alpha factor gene of the same transcription factor CBF (at 21q22 ), to another gene ETO (8q22). It is hypothesized that CBFB-MYH11 or AML1-ETO chimeric gene products may cause leukemia when expressed in hematopoietic progenitors. It is further hypothesized that the CBF transcription factor is of considerable importance in the regulation of hematopoiesis and may be involved in the pathogenesis of other leukemias. This project will aim to: l)Assess the effects on cell lines of expression of CBFB-MYH11 and AML1-ETO fusion proteins. Phenotypic changes including loss of differentiation, reversal of growth factor dependance, alterations in cell cycle and Cytosine Arabinoside sensitivity will be studied. 2) Test the effects of in vivo CBFB-MYH11 expression in mice or after retroviral transduction for expression in mouse bone marrow or via expression in transgenic animals. 3) Examine CBFB- MYH11 expression at various levels of hematopoietic differentiation and at various disease stages in patient samples. These experiments will define important biological and chemical properties of this novel chimeric gene and yield insights into the physiology of the normal CBF and its role in differentiation.

反转16（Inv16）和t（8; 21）染色体异常是 与特定疾病的形态和相对 急性骨髓性白血病的良好预后。基因编码 大约每个断点都被调查人员克隆为 具有由嵌合基因编码的融合cDNA。核心结合 因子（CBF-以前称为PEPB2）是异二聚体 由alpha和beta亚基CBF基因形成的转录因子 产品。 INV（16）导致5'编码序列的融合 CBFB（在16q22编码）到MYH11（肌球蛋白重链基因） 3'编码序列（16p13）。 t（8; 21）保险丝AML1，编码 同一转录因子CBF的α因子基因（在21q22 ），到另一个基因ETO（8Q22）。假设CBFB-MYH11 或AML1-Eto嵌合基因产物可能会引起白血病 在造血祖细胞中表达。 进一步 假设CBF转录因子是相当大的 在造血的调节中的重要性，可能参与 在其他白血病的发病机理中。该项目的目的是： l）评估对CBFB-MYH11和 AML1-ETO融合蛋白。表型变化，包括丢失 分化，增长因子依赖性的逆转，改变 在细胞周期和胞质阿拉伯糖苷的敏感性中 研究。 2）测试体内CBFB-MYH11表达在中的影响 小鼠或逆转录病毒后用于小鼠骨骼的表达 骨髓或通过转基因动物的表达。 3）检查CBFB- MYH11表达各种造血的水平 分化和在患者样本中的各种疾病阶段。 这些实验将定义重要的生物学和化学 这个新颖的嵌合基因的特性，并产生洞察力 正常CBF的生理学及其在分化中的作用。