The Role of Telomere Shortening in MDS-AML Pathogenesis (resubmission)

描述（由申请人提供）：端粒对于维持基因组完整性至关重要。先天性角化不良（DC）是一种以端粒短为特征的易患癌症的综合征。受影响的患者患血液系统恶性肿瘤的风险增加，特别是骨髓增生异常综合征（MDS）和急性髓系白血病（AML）。虽然 DC 是一种遗传性孟德尔疾病，但只有三分之二的家庭可以识别出端粒酶和端粒成分的种系突变，而其余病例中的因果突变则没有特征。 DC 基因突变也是 MDS 和 AML 家族子集遗传的基础。这一事实，再加上MDS-AML患者端粒较短的观察结果，表明端粒长度在这些疾病的遗传学中起着密切的作用。该项目研究了与了解 MDS-AML 发病机制相关的 DC 遗传学和生物学的两个方面。我们的目标是通过研究我们建立的注册表中遗传上未表征的 DC 家族来识别对端粒维持至关重要的新基因。鉴于传统连锁方法在小亲属中的已知局限性，我们编制的队列为应用下一代测序技术进行基因发现提供了理想的环境。在目标 2 中，我们研究了短端粒在我们表征的 DC 动物模型中促进 MDS-AML 的生物学特性。该小鼠模型独特地再现了人类端粒长度动态。拟议的 DC 研究对于理解 MDS-AML 的生物学具有特别重要的意义，因为 DC 患者中发现的端粒缺陷普遍随年龄增长而出现，而 MDS-AML 发病率随年龄增长而增加的生物学机制尚不清楚。从广义上讲，它们对于理解有关端粒长度在癌症风险和进展中的作用的基本问题具有重要意义。

DESCRIPTION (provided by applicant): Telomeres are essential for the maintenance of genomic integrity. Dyskeratosis congenita (DC) is a cancer- prone syndrome characterized by short telomeres. Affected patients have an increased risk for developing hematologic malignancies, specifically myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). While DC is an inherited Mendelian disorder, germline mutations in telomerase and telomere components are identifiable in only two-thirds of families, leaving the causal mutations in the remaining cases uncharacterized. Mutations in DC genes also underlie inheritance in a subset of MDS and AML families. This fact, along with the observation that MDS-AML patients have short telomeres, has suggested an intimate role for telomere length in the genetics of these disorders. This project examines two aspects of DC genetics and biology of relevance to understanding MDS-AML pathogenesis. We aim to identify novel genes that are critical for telomere maintenance by studying genetically uncharacterized DC families in a registry we have established. Given the known limitations of traditional linkage approaches in small kindreds, the cohort we have compiled provides an ideal setting to apply next-generation sequencing technologies for the purpose of gene discovery. In Aim 2, we examine the biology by which short telomeres promote MDS-AML in an animal model of DC we have characterized. This murine model uniquely recapitulates human telomere length dynamics. The proposed studies in DC have particular significance for understanding the biology of MDS-AML since the telomere defect found in DC patients is universally acquired with aging, and the biology that underlies the increasing incidence of MDS-AML with age is not understood. Broadly, they have implications for understanding fundamental questions regarding the role of telomere length in cancer risk and progression.