Molecular genetics of MLL-associated leukemia

MLL 相关白血病的分子遗传学

• 批准号: 6958391
• 负责人: MANUEL ORESTES DIAZ
• 金额: $ 118.78万
• 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/6958391
• 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）：该程序项目的重点是对MLL相关的白血病的研究。 长期的目标是了解“与涉及cliromosome 11频带Q23的翻译产生的与MLL融合基因相关的白血病的过程。 这些白血病包括几个子集：新成年和小儿白血病，治疗相关的白血病，其治疗其他癌症患有拓扑异构酶 - II抑制剂的癌症以及显然在子宫中显然出现的婴儿白血病。 项目1和2将解决白血病过程的启动和进展的各个方面：项目1将探讨凋亡核酸酶的假设在染色体11易位的产生中起着重要作用，这些易位在治疗相关的白血病和婴儿白血病中启动白血病过程。 它还将寻找突变，使细胞在进行重排后能够生存，并在接受细胞毒性疗法的人类患者中寻找MLL重排。 项目2将尝试识别使用动物模型将启动克隆推向可检测到的临床可检测的白血病的二级突变。 MLL的融合蛋白保存了MLL的N末端部分，并用伴侣蛋白的融合蛋白代替其C末端部分。 项目2还将尝试剖析MLL的这些不同领域，以确定哪些对哪些域对转化至关重要，哪些是抑制性的。 项目3将提出一个相关的问题，该问题测试了以下假设：CYP33是结合MLL的第三个PHD手指的蛋白质，它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作为在MLL的基因间区域中产生的非编码RNA的传感器的作用，靶基因也将在项目3中研究。项目4将测试MLL通过其启动子和增强子的组蛋白和染色质结构的修饰来调节其靶基因的假设。 它还将研究MLL蛋白本身的可能性修饰（即乙酰化）的可能性修饰（即乙酰化），将其作为靶基因的反式激活剂的功能调节。 逆转录病毒核心将为这些项目提供帮助。 这些研究将更好地理解白血病过程及其与造血过程的关系，通过表观遗传过程及其与遗传突变的破坏。 这些研究的结果可能允许设计新的预防和治疗策略。