ROLE OF REPLICATION STRESS DURING MYC-DEPENDENT LYMPHOMAGENESIS

描述(由申请人提供)：c-Myc原癌基因的非调控表达是许多人类癌症发展的常见必要条件。尽管对其生物学有广泛的了解，但我们仍然不知道维持其致癌活性的确切分子机制。Myc在原代细胞和转基因小鼠B细胞中的表达一旦解除，其对DNA复制启动的生理控制作用就会放大，从而导致复制压力和随后的DNA损伤。复制应激是一种在不同组织来源的早期癌症中常见的现象，被认为是癌基因激活的结果。然而，它在肿瘤发生过程中的要求的正式证据还没有得到。这个项目的长期目标是表征依赖Myc的复制应激对B细胞淋巴瘤发生的贡献。我们将具体评估改变Myc促进复制应激的能力-通过消除其控制DNA复制的能力或改变细胞对Myc依赖的复制应激的反应-是否决定致癌过程的结果。我们假设，应对复制应激的途径抑制了由原癌基因驱动的肿瘤启动，因此，当B细胞解除调控时，对这些途径的操纵将决定Myc发生淋巴瘤的能力。 本研究计划是职业发展计划的一部分，通过该计划，我旨在获得以下方面的关键知识和技术技能：(1)应用小鼠模型研究癌症的发生和发展；以及(2)使用高通量技术和系统生物学来解决癌症领域的一般性问题，由于其复杂性，需要采用综合方法。主办中心的非同寻常的特点确保了培训期间的最佳环境，所有这些学科都被整合到癌症研究中。因此，指导阶段将使我成功地过渡到独立阶段，在那里继续开发这项研究项目的最后部分，获得上述提出的研究假设的原则证据，并继续研究依赖Myc的B细胞淋巴瘤的基本机制，旨在为这类疾病找到新的治疗靶点。 公共卫生相关性：70%以上的人类癌症会失去对Myc蛋白活性的正常控制，这对癌症的发生、生长和发展是必不可少的。该项目建议研究在肿瘤发展过程中Myc用来控制细胞增殖的新机制的需求。这一要求的确认将表明这一功能将成为大多数癌症类型的潜在新治疗靶点。

DESCRIPTION (provided by applicant): Deregulated expression of the c-Myc protooncogene is a frequent requisite for the development of many human cancers. Despite extensive knowledge of its biology, we are still unaware of the precise molecular mechanisms that sustain its oncogenic activity. Amplification of the physiologic control of DNA replication initiation by Myc upon deregulation of its expression in primary cells and transgenic mouse B-cells causes replication stress and subsequent DNA damage. Replication stress is a phenomenon often seen in early cancers from different tissue origin, and it is believed to be consequent to oncogene activation. However, formal proof for its requirement during tumorigenesis is yet to be obtained. The long-term goal of this project is to characterize the contribution of Myc-dependent replication stress to B-cell lymphomagenesis. We will specifically assess whether altering Myc's ability to promote replication stress - by either ablating its ability to control DNA replication or modifying the cellular responses to Myc- dependent replication stress- determines the outcome of the oncogenic process. We hypothesize that pathways coping with replication stress restrain tumor initiation driven by this protooncogene and hence, manipulation of these pathways will determine Myc's ability to generate lymphomas when deregulated in B-cells. This Research Plan is meant to be part of a Career Development Plan through which I aim to obtain critical knowledge and technical skills on: (1) the application of mouse models to the study cancer initiation and progression; and (2) the use of high- throughput technologies and Systems Biology to address general questions in the cancer field that, due to their complexity, require integrated approaches. The extraordinary characteristics of the host center, where all these disciplines are integrated for the study of cancer, ensure an optimal environment for the training period. The mentored phase will therefore allow me to transit with success to an independent phase, where to continue to develop the final parts of this research project, obtain proof of principle for the above proposed research hypothesis, and pursue the study of the basic mechanisms of Myc-dependent B-cell lymphomagenesis, with aim to find novel therapeutic targets for this group of diseases. PUBLIC HEALTH RELEVANCE: Loss of normal control of Myc protein activity occurs in more than 70% of human cancers, and is essential for their initiation, growth and progression. This project proposes to examine the requirement during tumor development of a novel mechanism used by Myc to control cellular proliferation. Confirmation of this requirement will point to this function as a potential novel therapeutic target in a majority of cancer types.