Molecular genetics of MLL-associated leukemia

描述(申请人提供)：本项目的重点是MLL相关白血病发生的研究。我们的长期目标是了解与MLL融合基因相关的白血病发生过程，这些融合基因是由涉及剪粒11带q23的翻译而产生的。这些白血病包括几个亚型：初发成人和儿童白血病，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，以及明显出现在子宫中的婴儿白血病。项目1和项目2将讨论白血病形成过程的启动和进展的各个方面：项目1将探索这样的假设，即凋亡核酸酶在11号染色体易位的产生中发挥重要作用，该易位在治疗相关白血病和婴儿白血病中都启动了白血病过程。它还将寻找允许细胞在经历重排后存活于凋亡的突变，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识别将启动的克隆推入临床可检测到的白血病的次级突变。MLL的融合蛋白保留了MLL的N端部分，而将其C端部分替换为伙伴蛋白的C端部分。项目2也将试图剖析MLL的这些不同的结构域，以确定哪些是必不可少的，哪些是转化的抑制因素。项目3将提出一个相关的问题，以检验以下假设：Cyp33是一种结合MLL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来抑制MLL的反式激活活性。Cyp33作为MLL基因间隔区产生的非编码RNA的传感器的作用也将在项目3中进行研究。项目4将检验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MAT修饰(即：乙酰化)调节其作为目标基因反式激活因子的功能的可能性。逆转录病毒核心将为这些项目提供帮助。这些研究将更好地了解白血病的发生过程及其与表观遗传过程和基因突变破坏造血调控的关系。这些研究的结果可能会使设计新的预防和治疗策略成为可能。

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.