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: 10221642
• 负责人: Agnel Sfeir
• 金额: $ 42.67万
• 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/10221642
• 关键词: Address; Affect; Attenuated; Biological Assay; Bypass; CRISPR interference; Cancer Patient; Cell Proliferation; Cells; Chronic Lymphocytic Leukemia; Common Lymphoid Progenitor; Cutaneous T-cell lymphoma; Data; Defect; Development; Fostering; Functional disorder; Genetic Screening; Genomic Instability; Glioma; Goals; Human; Immunocompromised Host; Lead; Libraries; Lymphoma cell; Malignant Neoplasms; Missense Mutation; Modeling; Monitor; Mus; Mutate; Mutation; Oncogenes; Parathyroid Adenoma; Patients; Phenotype; Primary Neoplasm; Proliferating; Reporting; Role; Signal Transduction; T-Cell Lymphoma; TP53 gene; Telomere-Binding Proteins; Testing; Thymic Lymphoma; Transplantation; Tumor Suppressor Proteins; Tumor-Derived; attenuation; base; cancer cell; cancer genome; chromosome fusion; driver mutation; experimental study; functional genomics; genome-wide; in vivo; melanoma; mouse model; neoplastic cell; next generation sequencing; novel; novel strategies; patient stratification; replication stress; stem cells; telomere; therapeutic target; therapeutically effective; tumor; tumor progression; tumorigenesis

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 这项提议的目的是研究端粒的改变 结合蛋白POT1导致肿瘤发生。POT1突变（>100）与 与几种类型的人类癌症，如慢性淋巴细胞白血病（CLL），皮肤T 细胞淋巴瘤（CTCL）、套细胞淋巴瘤、甲状旁腺腺瘤、神经胶质瘤和 黑素瘤。我们的初步数据表明，POT1的扰动导致复制压力， 端粒和端粒功能障碍。此外，我们已经表明，抑制POT1在 普通淋巴祖细胞（CLP）促进小鼠胸腺淋巴瘤的形成。 在这里，我们将测试我们的假设，POT1突变触发端粒复制应激， 转基因导致基因组不稳定和癌症的发展。此外，我们会处理 使具有POT1突变的癌细胞能够绕过端粒复制应激的机制 并无限增殖。最后，我们将开发一种遗传筛查来询问POT1突变， 并鉴定驱动突变。总之，我们的研究将提供一个重要的步骤， 以确定新的和有效的治疗靶点来治疗越来越多的癌症 POT1突变的患者。