Molecular genetics of MLL-associated leukemia

描述（由申请人提供）：本项目的重点是研究MLL相关的白血病发生。长期目标是了解与mll融合基因相关的白血病发生过程，这是由涉及11条带q23的染色体翻译引起的。这些白血病包括几个亚群：新生成人和儿童白血病，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，以及明显在子宫内发生的婴儿白血病。项目1和项目2将探讨白血病发生过程的开始和进展方面：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。它还将寻找允许细胞在经历重排后存活的突变，并将在接受细胞毒性治疗的人类患者中寻找MLL重排。项目2将尝试利用动物模型确定将启动克隆推向临床可检测白血病的继发性突变。MLL的融合蛋白保留了MLL的n端部分，并用伙伴蛋白的c端部分取代了MLL的c端部分。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。Project 3将提出一个相关的问题来验证Cyp33这个结合MLL第三个PHD指的蛋白通过控制MLL抑制域的功能及其对靶基因染色质结构的影响来抑制MLL反激活活性的假设。Cyp33作为MLL靶基因基因间区产生的非编码rna的传感器的作用也将在项目3中进行研究。项目4将测试MLL通过修饰其启动子和增强子的组蛋白和染色质结构来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）调节其作为靶基因反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。这些研究将更好地了解白血病的发生过程及其与表观遗传过程的造血调节和基因突变的破坏之间的关系。这些研究的结果可能有助于设计新的预防和治疗策略。

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.