ROLE OF REPLICATION STRESS DURING MYC-DEPENDENT LYMPHOMAGENESIS

描述（由申请人提供）：c-Myc原癌基因的表达失调是许多人类癌症发展的必要条件。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精确分子机制。在原代细胞和转基因小鼠b细胞中，Myc的表达被解除后，对DNA复制起始的生理控制被放大，导致复制应激和随后的DNA损伤。复制应激是一种常见于不同组织来源的早期癌症的现象，它被认为是癌基因激活的结果。然而，在肿瘤发生过程中对其要求的正式证据尚未获得。该项目的长期目标是表征myc依赖性复制应激对b细胞淋巴瘤形成的贡献。我们将具体评估是否改变Myc促进复制应激的能力——通过削弱其控制DNA复制的能力或修改细胞对Myc依赖性复制应激的反应——决定了致癌过程的结果。我们假设，应对复制应激的途径抑制了由该原癌基因驱动的肿瘤起始，因此，当Myc在b细胞中失控时，对这些途径的操纵将决定Myc产生淋巴瘤的能力。

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.