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。先天性角化不良症（DC）是一种以端粒短为特征的易癌综合征。受影响的患者发生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）和急性髓性白血病（AML）。虽然DC是一种遗传性孟德尔疾病，但端粒酶和端粒成分的种系突变仅在三分之二的家庭中可识别，其余病例的因果突变尚未确定。DC基因突变也是MDS和AML家族中一部分遗传的基础。这一事实，加上观察到MDS-AML患者端粒较短，表明端粒长度在这些疾病的遗传学中起着密切的作用。本项目研究了DC遗传学和生物学的两个方面，以了解MDS-AML的发病机制。我们的目标是通过在我们建立的注册表中研究基因未表征的DC家族来鉴定对端粒维持至关重要的新基因。考虑到传统连锁方法在小型物种中的已知局限性，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Aim 2中，我们研究了在我们表征的DC动物模型中，短端粒促进MDS-AML的生物学。这种小鼠模型独特地概括了人类端粒长度动态。由于DC患者发现的端粒缺陷普遍随年龄增长而获得，而MDS-AML发病率随年龄增长而增加的生物学机制尚不清楚，因此在DC中提出的研究对于了解MDS-AML的生物学具有特别的意义。总的来说，它们对理解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.