ANALYSIS OF MULTIPLE CHIMERIC TRANSCRIPTS IN THE T(3;21)

T(3;21)中多个嵌合转录物的分析

• 批准号: 6493553
• 负责人: Giuseppina Nucifora
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-13 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6493553
• 关键词: DNA replication; acute myelogenous leukemia; carcinogenesis; cell differentiation; chimeric proteins; chromosome translocation; chronic myelogenous leukemia; fusion gene; gene deletion mutation; gene induction /repression; genetic library; genetic mapping; genetic transcription; hematopoiesis; human genetic material tag; human tissue; neoplasm /cancer genetics; oncogenes; reporter genes; tissue /cell culture; transcription factor

The recurring chromosomal translocation (3;21)(q26;q22) has been associated with de novo or therapy related acute and chronic myeloid leukemias. This translocation is unusual in that it results in three different fusion genes. The role of each fusion gene is not known. One of them, AML1/MDS1/EVI1, results from the in-frame joining of two transcription activators following the translocation. They are AML1, which is necessary to fetal liver hematopoiesis and is located at chromosome band 21q22, and MDS1/EVI1, located at chromosome band 3q26. MDS1/EVI1 is not detected in hematopoietic tissues, but is transiently expressed in differentiating hematopoietic stem cells. In contrast to AML1 and MDS1/EVI1, which are very strong transcription activators, AML1/MDS1/EVI1 is a repressor, and can inhibit promoters activated by AML1 and MDS1/EVI1. The objective of this proposal is to dissect the molecular mechanisms by which the fusion protein AML1/MDS1/EVI1 alters the progress of the hematopoietic differentiation leading to leukemia. We have developed several models showing that, in hematopoietic precursor cells, AML1/MDS1/EVI1 inhibits the response to factors that control cell replication and differentiation. Based on preliminary results, we hypothesize that the fusion protein acts by disrupting the normal regulation of genes regulated by AML1 and MDS1/EVI1 during hematopoiesis, resulting in inappropriate level of expression of lineage- specific factors critical for hematopoietic differentiation and replication. The questions addressed in this proposal are: How is the repression mediated, and what are the targets of the fusion protein? By using a combination of biochemical and molecular techniques, and tissue culture studies, we will identify the target proteins regulated by AML1/MDS1/EVI1 and assess their role in cell transformation. The information we obtain will be useful in the design of new treatments for patients with myeloid leukemia and a t(3;21). In addition, our results will provide insight in the study of leukemias in which either AML 1 or MDS1/EVI1 are rearranged.

反复发生的染色体易位 (3;21)(q26;q22) 与新发或治疗相关的急性和慢性粒细胞白血病有关。 这种易位的不同寻常之处在于它产生了三个不同的融合基因。每个融合基因的作用尚不清楚。 其中之一，AML1/MDS1/EVI1，是由易位后两个转录激活子的框内连接产生的。 它们是胎儿肝脏造血所必需的 AML1，位于染色体带 21q22，以及 MDS1/EVI1，位于染色体带 3q26。 MDS1/EVI1在造血组织中未检测到，但在分化的造血干细胞中短暂表达。 与 AML1 和 MDS1/EVI1 等非常强的转录激活因子相比，AML1/MDS1/EVI1 是一种抑制因子，可以抑制 AML1 和 MDS1/EVI1 激活的启动子。该提案的目的是剖析融合蛋白 AML1/MDS1/EVI1 改变导致白血病的造血分化进程的分子机制。 我们开发了多个模型，表明在造血前体细胞中，AML1/MDS1/EVI1 抑制对控制细胞复制和分化的因子的反应。 根据初步结果，我们假设融合蛋白通过破坏造血过程中受 AML1 和 MDS1/EVI1 调节的基因的正常调节而发挥作用，导致对造血分化和复制至关重要的谱系特异性因子的表达水平不适当。 该提案解决的问题是：抑制是如何介导的，以及融合蛋白的靶标是什么？ 通过结合生化和分子技术以及组织培养研究，我们将鉴定受 AML1/MDS1/EVI1 调节的靶蛋白，并评估它们在细胞转化中的作用。 我们获得的信息将有助于为髓系白血病和 t(3;21) 患者设计新的治疗方法。 此外，我们的结果将为 AML 1 或 MDS1/EVI1 重排的白血病研究提供见解。