Role of Replication Stress during Myc-dependent Lymphomagenesis

项目总结/摘要（30行） c-Myc原癌基因的表达失调是肿瘤发生的常见条件。 许多人类癌症的发展。尽管我们对它的生物学有广泛的了解， 仍然不知道维持其致癌活性的精确分子机制。 Myc对DNA复制起始的生理控制的扩增 其在原代细胞和转基因小鼠B细胞中表达的失调导致 复制应激和随后的DNA损伤。复制压力是一种现象 通常见于不同组织来源的早期癌症， 致癌基因激活的结果。然而，在此期间， 肿瘤发生尚未获得。该项目的长期目标是描述 Myc依赖性复制应激对B细胞淋巴瘤发生的作用。我们将 具体评估是否改变Myc的能力，以促进复制应激-通过 消除其控制DNA复制的能力或改变细胞对Myc的反应， 依赖性复制应激-决定致癌过程的结果。我们 假设应对复制应激途径抑制肿瘤起始驱动 因此，操纵这些通路将决定Myc的 B细胞失调时产生淋巴瘤的能力。 本研究计划是职业发展计划的一部分， 旨在获得以下关键知识和技术技能：（1）鼠标的应用 研究癌症起始和进展的模型;和（2）使用高- 通量技术和系统生物学来解决癌症中的一般问题， 这些领域由于其复杂性，需要采取综合办法。的非凡 主办中心的特点，在那里所有这些学科都集成了研究 癌症，确保训练期间的最佳环境。指导阶段 因此，将使我能够成功地过渡到一个独立的阶段， 继续开发该研究项目的最后部分，获得原理证明， 提出上述研究假设，并进行基本机制的研究 Myc依赖性B细胞淋巴瘤的发生，旨在寻找新的治疗靶点 对于这类疾病。

PROJECT SUMMARY/ABSTRACT (30 LINES) 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.