Replicative Senescence as a Tumor Suppressive Mechanism

复制衰老作为肿瘤抑制机制

• 批准号: 8837573
• 负责人: Sandy S Chang
• 金额: $ 30.69万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-08 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837573
• 关键词: 13q; 17p; Address; Age; Apoptosis; Automobile Driving; Binding Proteins; Cell Aging; Cell Cycle Arrest; Cell Line; Cells; Characteristics; Checkpoint kinase 1; Chromosomes; Chronic Lymphocytic Leukemia; Clinical; Clonal Evolution; Complex; Country; DNA; DNA Damage; Diagnosis; Disease; Excision; Functional disorder; Future; Genes; Genetic; Genome; Genomic Instability; Genomics; Health; Hematopoietic stem cells; Human; Human Genetics; Incidence; Knockout Mice; Length; Lesion; Malignant Neoplasms; Measures; Mediating; Modeling; Mus; Mutation; Neoplasm Metastasis; Outcome; Patau' s syndrome; Pathogenesis; Pathway interactions; Patients; Play; Population; Proteins; Repression; Role; SS DNA BP; Sampling; Severity of illness; Structural Chromosomal Abnormality; Telomere Maintenance; Telomere-Binding Proteins; Testing; Time; Tissues; Treatment Efficacy; adult leukemia; base; cancer initiation; del(11q); disease classification; exome sequencing; homologous recombination; inhibitor/antagonist; innovation; mouse model; mutant; new therapeutic target; novel; prevent; reconstitution; response; small hairpin RNA; telomere; tool; trait; tumor; tumor progression

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia is the most common adult leukemia in Western countries, with an estimated incidence of 3.9 per 100,000 people in the US and a median age of 72 years at time of diagnosis. A characteristic feature of this disease is its strikingly complex genomic profiles, highlighted by chromosome structural aberrations involving loss of chromosomes 11q, 13q, 17p and trisomy 13 [4,5]. These complex genetic alterations are thought to arise due to the stepwise accumulation of mutational changes in favor of tumor progression, initially in a genetically heterogeneous cell population, then by selection of more aggressive traits, such as the ability to metastasize into surrounding tissues. One important mechanism that protects against the acquisition of an unstable genome is proper function of telomeres, protein-DNA complexes that cap the ends of chromosomes. Dysfunctional telomeres undergo end-to-end chromosome fusions, resulting in an unstable genome observed in many diverse human cancers, including CLL. We hypothesize that telomere dysfunction in hematopoietic stem cells (HSCs) results in telomere dysfunction, driving genomic instability that results in the stepwise accumulation of mutational changes in favor of cancer progression, including the selection of p53 mutations during clonal evolution and progression to CLL. To test this hypothesis, we have generated a novel conditional knockout mouse model to delete mPOT1a/b in hematopoietic stem cells. As pioneers in the study of the role of POT1 in telomere end protection, we will utilize this highly innovative genetic tool, as wel as human CLL samples, to investigate the role of hPOT1 in CLL pathogenesis.

描述（由申请人提供）：慢性淋巴细胞白血病是西方国家最常见的成人白血病，在美国估计发病率为每 10 万人中 3.9 人，诊断时的中位年龄为 72 岁。这种疾病的一个典型特征是其极其复杂的基因组谱，突出表现为染色体结构畸变，涉及染色体 11q、13q、17p 和 13 三体性的丢失 [4,5]。这些复杂的遗传改变被认为是由于有利于肿瘤进展的突变变化的逐步积累而产生的，最初是在遗传异质的细胞群中，然后通过选择更具攻击性的特征，例如转移到周围组织的能力。防止获得不稳定基因组的一个重要机制是端粒的正常功能，端粒是覆盖染色体末端的蛋白质-DNA 复合物。功能失调的端粒经历端到端染色体融合，导致在许多不同的人类癌症（包括慢性淋巴细胞性白血病）中观察到不稳定的基因组。我们假设造血干细胞 (HSC) 中的端粒功能障碍会导致端粒功能障碍，从而驱动基因组不稳定，从而导致有利于癌症进展的突变变化的逐步积累，包括克隆进化和进展为 CLL 期间 p53 突变的选择。为了验证这一假设，我们构建了一种新型条件敲除小鼠模型，以删除造血干细胞中的 mPOT1a/b。作为研究 POT1 在端粒末端保护中的作用的先驱，我们将利用这种高度创新的遗传工具以及人类 CLL 样本来研究 hPOT1 在 CLL 发病机制中的作用。