Define the Role of POT1 Mutation in Genome Instability and Cancer

定义 POT1 突变在基因组不稳定性和癌症中的作用

• 批准号: 10379657
• 负责人: Agnel Sfeir
• 金额: $ 20.1万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379657
• 关键词: Define; Role; POT1; Mutation; Genome

Project Summary The goal of this proposal is to investigate the mechanism by which alteration in the telomere binding protein POT1 results in tumorigenesis. Mutations in POT1 (>100) have been associated with several types of human cancers such as chronic lymphocytic leukemia (CLL), cutaneous T cell lymphomas (CTCL), mantel cell lymphomas, parathyroid adenomas, gliomas, and melanomas. Our preliminary data indicate that perturbations in POT1 lead to replication stress at telomeres and telomere dysfunction. Moreover, we have shown that inhibition of POT1 in the common lymphoid progenitor cells (CLPs) promotes the formation of thymic lymphomas in mice. Here we will test our hypothesis that POT1 mutations trigger telomere replication stress which in turn leads to genome instability and cancer development. In addition, we will address the mechanism that enables cancer cells with POT1 mutations to bypass telomere replication stress and proliferate indefinitely. Lastly, we will develop a genetic screen to interrogate POT1 mutations in vivo and identify driver-mutations. In conclusion, our study will provide an important step towards identifying novel and effective therapeutic targets to treat an increasing number of cancer patients with POT1 mutations.

项目摘要 该提议的目的是研究端粒改变的机制 结合蛋白POT1导致肿瘤发生。 POT1（> 100）中的突变已关联 有几种类型的人类癌症，例如慢性淋巴细胞性白血病（CLL），皮肤T 细胞淋巴瘤（CTCL），壁炉壁细胞淋巴瘤，甲状旁腺腺瘤，神经胶质瘤和 黑色素瘤。我们的初步数据表明，POT1的扰动导致复制应力 端粒和端粒功能障碍。此外，我们已经表明了对Pot1的抑制 常见的淋巴样祖细胞（CLP）促进了小鼠胸腺淋巴瘤的形成。 在这里，我们将测试我们的假设，即POT1突变引发端粒复制应力，这在 转弯会导致基因组不稳定性和癌症发展。此外，我们将解决 使pot1突变癌细胞绕过端粒复制应力的机制 并无限期地扩散。最后，我们将开发一个遗传屏幕来询问POT1突变 体内并识别驾驶员 - 撞击。总之，我们的研究将提供一个重要的步骤 要识别新颖有效的治疗靶标，以治疗越来越多的癌症 患有POT1突变的患者。