Molecular genetics of MLL-associated leukemia

MLL 相关白血病的分子遗传学

• 批准号: 7127116
• 负责人: MANUEL ORESTES DIAZ
• 金额: $ 12.4万
• 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/7127116
• 关键词: Molecular; genetics; MLL; associated; leukemia

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 translocations involving chromosome 11 band q23. These leukemia's 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 I 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 Tran activating 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 that modifications (i.e: acetylation) of the MLL protein itself modulate its function as a trans-activator of the target genes. A DNA-Microarray Core and 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.

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。长期目标是了解与涉及11条带染色体Q23的易位引起的与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：新的成人和小儿白血病，治疗相关的白血病，此后其他癌症酶II抑制剂治疗其他癌症，以及在子宫内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：项目一世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了白血病过程。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的这些不同域以确定哪些是 对哪些是必不可少的，哪些是转化的抑制。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，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，抑制MLL的TRAN激活活性。 在项目3中，还将研究CYP33作为MLL靶基因基因间区域中非编码RNA的传感器的作用。项目4将测试MLL通过在其启动子和增强子的组蛋白和染色质结构中修饰的MLL调节其靶基因的假设。它还将研究MLL蛋白本身的修饰（即：乙酰化）的可能性调节其作为靶基因的反式激活剂的功能。 DNA微阵列核心和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。