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

基本信息

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
项目类别：
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

项目摘要

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。