Replicative Senescence as a Tumor Suppressive Mechanism

描述(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，在美国的发病率估计为每10万人3.9人，确诊时的中位年龄为72岁。该病的一个特征是其非常复杂的基因组图谱，突出表现为染色体结构异常，包括染色体11q、13q、17p和13三体[4，5]的丢失。这些复杂的基因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，最初是在遗传异质性的细胞群体中，然后是通过选择更具侵袭性的特征，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适当功能，端粒是覆盖在染色体末端的蛋白质-DNA复合体。功能失调的端粒经历端到端的染色体融合，导致在许多不同的人类癌症中观察到不稳定的基因组，包括CLL。我们假设，造血干细胞(HSCs)中的端粒功能障碍会导致端粒功能障碍，从而驱动基因组的不稳定，从而导致有利于癌症进展的突变变化的逐步积累，包括在克隆进化和进展到CLL期间选择P53突变。为了验证这一假设，我们建立了一种新的条件基因敲除小鼠模型，以删除造血干细胞中的mPOT1a/b。作为研究POT1在端粒末端保护中作用的先驱，我们将利用这一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。

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.