Define the Role of POT1 Mutation in Genome Instability and Cancer

项目摘要 这项提议的目的是研究端粒改变的机制 结合蛋白POT1导致肿瘤的发生。POT1(&gt；100)的突变已被关联 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 细胞性淋巴瘤(CTCL)、套细胞淋巴瘤、甲状旁腺腺瘤、胶质瘤和 黑色素瘤。我们的初步数据表明，POT1中的扰动导致复制压力在 端粒和端粒功能障碍。此外，我们已经证明，POT1在细胞内的抑制 共同淋巴祖细胞(CLPs)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，即POT1突变触发端粒复制应激，这在 转而导致基因组不稳定和癌症的发展。此外，我们还将解决 POT1突变的癌细胞绕过端粒复制应激的机制 并无限期地扩散。最后，我们将开发一种基因筛查来询问POT1突变 并确定驱动突变。总之，我们的研究将提供重要的一步 寻找新的和有效的治疗靶点来治疗越来越多的癌症 存在POT1突变的患者。

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.