Molecular genetics of MLL-associated leukemia

MLL 相关白血病的分子遗传学

• 批准号: 7460972
• 负责人: MANUEL ORESTES DIAZ
• 金额: $ 12.78万
• 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/7460972
• 关键词: Acetylation; Address; Adult; Animal Model; Apoptosis; Apoptotic; C-terminal; Cells; Childhood; Chimeric Proteins; Chromatin Structure; Chromosomes, Human, Pair 11; Cytotoxic Chemotherapy; DNA Sequence Rearrangement; Disruption; Enhancers; Epigenetic Process; Functional RNA; Gene Mutation; Gene Targeting; Generations; Goals; HRX protein; Hematopoiesis; Histones; Human; Infant; Intercistronic Region; Malignant Neoplasms; Modification; Molecular Genetics; Mutation; N-terminal; PHD Finger; Patients; Performance; Play; Prevention; Process; Protein Binding; Proteins; Regulation; Repression; Role; Testing; Therapeutic; Topoisomerase; Trans-Activators; Translations; design; fusion gene; in utero; leukemia; leukemogenesis; nuclease; programs; promoter; sensor

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。 长期的目标是了解白血病发生的过程与MLL融合基因的翻译所产生的涉及染色体11带q23。 这些白血病包括几个子集：新生成人和儿童白血病，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和项目2将讨论白血病发生过程的启动和进展方面：项目1将探讨凋亡核酸酶在11号染色体易位的产生中发挥重要作用的假设，该易位在治疗相关白血病和婴儿白血病中启动白血病过程。 它还将搜索允许细胞在经历重排后存活凋亡的突变，并将搜索接受细胞毒性治疗的人类患者中的MLL重排。 项目2将尝试使用动物模型来识别将初始克隆推向临床可检测的白血病的继发突变。 MLL的融合蛋白保留了MLL的N-末端部分，并将其C-末端部分替换为来自伴侣蛋白的部分。 项目2还将尝试剖析MLL的这些不同结构域，以确定哪些是必不可少的，哪些是抑制转化的。 项目3将提出一个相关的问题，检验Cyp 33（一种结合MLL的第三个PHD指的蛋白质）通过控制其阻遏结构域的功能及其对靶基因染色质结构的影响来抑制MLL的反式激活活性的假设。 Cyp 33作为MLL基因间区域产生的非编码RNA的传感器的作用，靶基因也将在项目3中研究。 项目4将检验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。 它还将考虑修改的可能性（即：MLL蛋白本身的乙酰化）调节其作为靶基因反式激活因子的功能。 逆转录病毒核心将为这些项目提供帮助。 这些研究将提供一个更好的了解白血病的过程和它的关系，造血调控的表观遗传过程和破坏的基因突变。 这些研究的结果可能有助于设计新的预防和治疗策略。