Molecular genetics of MLL-associated leukemia

MLL 相关白血病的分子遗传学

• 批准号: 7125493
• 负责人: MANUEL ORESTES DIAZ
• 金额: $ 117.15万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-23 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125493
• 关键词: carcinogenesis; chromosome translocation; clinical research; fusion gene; leukemia; molecular genetics; neoplasm /cancer genetics

DESCRIPTION (provided by applicant): The focus of this program project is the study of MLL associated leukemogenesis. The long-term goal is to understand 'the process of leukemogenesis associated with MLL-fusion genes resulting from translations involving cliromosome 11 band q23. These leukemias include several subsets: de novo adult and pediatric leukemia, therapy-related leukemia subsequent to treatment of other cancers with topoisomerase-II inhibitors, and infant leukemia that apparently arise in utero. Projects 1 and 2 will address aspects of the initiation and progression of the leukemogenic process: Project 1 will explore the hypothesis that apoptotic nucleases play a significant role in the generation of the chromosome 11 translocations that initiate the leukemic process both in treatment related leukemia and in infant leukemia. It will also search for mutations that allow cells to survive apoptosis after undergoing rearrangements, and will search for MLL rearrangements in human patients subjected to cytotoxic therapy. Project 2 will try to identify secondary mutations that push the initiated clones into clinically detectable leukemia using animal models. The fusion proteins of MLL conserve the N-terminal part of MLL, and replace its C-terminal part with one from the partner proteins. Project 2 will also try to dissect these different domains of MLL to determine which ones are essential for, and which ones are inhibitory of transformation. Project 3 will ask a related question testing the hypothesis that Cyp33, a protein that binds the third PHD finger of MLL, inhibits the transactivating activity of MLL by controlling the function of its repression domain and its effect on target gene chromatin structure. The role of Cyp33 as a sensor for non-coding RNAs generated in the intergenic regions of the MLL, target genes will also be studied in Project 3. Project 4 will test the hypothesis that MLL regulates its target genes through modifications in the histones and chromatin structure of their promoters and enhancers. It also will look at the possibility mat modifications (i.e.: acetylation) of the MLL protein itself modulate its function as a transactivator of the target genes. A Retroviral Core will provide help to these projects. These studies will provide a better understanding of the leukemogenic process and its relationship to hematopoiesis regulation by epigenetic processes and its disruption by genetic mutation. The results of these studies may allow the design of new prevention and therapeutic strategies.

描述（由申请人提供）：该项目的重点是 MLL 相关白血病发生的研究。 长期目标是了解“与涉及染色体 11 带 q23 翻译的 MLL 融合基因相关的白血病发生过程”。 这些白血病包括几个亚类：成人和儿童新发白血病、用拓扑异构酶-II 抑制剂治疗其他癌症后的治疗相关白血病，以及明显在子宫内出现的婴儿白血病。 项目 1 和 2 将讨论白血病发生过程的启动和进展的各个方面：项目 1 将探讨这样的假设：凋亡核酸酶在 11 号染色体易位的产生中发挥重要作用，而 11 号染色体易位在治疗相关白血病和婴儿白血病中启动白血病过程。 它还将寻找使细胞在经历重排后能够在凋亡中存活的突变，并将在接受细胞毒治疗的人类患者中寻找 MLL 重排。 项目 2 将尝试使用动物模型来识别二次突变，从而将启动的克隆推向临床可检测的白血病。 MLL 的融合蛋白保留了 MLL 的 N 端部分，并用伴侣蛋白中的一个取代了其 C 端部分。 项目 2 还将尝试剖析 MLL 的这些不同领域，以确定哪些领域对于转化至关重要，哪些领域对转化具有抑制作用。 项目 3 将提出一个相关问题，测试以下假设：Cyp33（一种结合 MLL 第三个 PHD 指的蛋白质）通过控制其抑制域的功能及其对靶基因染色质结构的影响来抑制 MLL 的反式激活活性。 Cyp33 作为 MLL 基因间区域生成的非编码 RNA 传感器的作用，目标基因也将在项目 3 中进行研究。项目 4 将测试 MLL 通过修改其启动子和增强子的组蛋白和染色质结构来调节其目标基因的假设。 它还将研究 MLL 蛋白本身的修饰（即乙酰化）调节其作为靶基因反式激活子的功能的可能性。 逆转录病毒核心将为这些项目提供帮助。 这些研究将有助于更好地了解白血病发生过程及其与表观遗传过程的造血调节及其基因突变破坏的关系。 这些研究的结果可能有助于设计新的预防和治疗策略。