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

端粒缩短在 MDS-AML 发病机制中的作用（重新提交）

• 批准号: 8246709
• 负责人: Mary Y Armanios
• 金额: $ 33.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246709
• 关键词: Accounting; Acute; Acute Myelocytic Leukemia; Affect; Age; Aging; Aging-Related Process; Animal Model; Biology; Biology of Aging; Cessation of life; Defect; Diagnosis; Diagnostic; Disease; Dyskeratosis Congenita; Dysmyelopoietic Syndromes; Enzymes; Evolution; Family; Family Leave; Feasibility Studies; Gene Mutation; Genes; Genetic; Genomic Instability; Genomics; Germ-Line Mutation; Goals; Hematologic Neoplasms; Hereditary Disease; Human; Incidence; Ineffective Hematopoiesis; Inherited; Knock-in Mouse; Length; Maintenance; Malignant Neoplasms; Modeling; Mus; Mutate; Mutation; Myeloproliferative disease; Oncogenic; Pancytopenia; Pathogenesis; Patients; Physiological; Predisposing Factor; Premature aging syndrome; Prevalence; Prevention; Recruitment Activity; Registries; Rest; Risk; Role; Stem cells; Syndrome; System; Technology; Telomerase; Telomerase RNA Component; Telomere Maintenance; Telomere Shortening; Testing; United States; Virulent; Work; base; cancer risk; cohort; exome; gene discovery; genetic risk factor; hTR RNA; improved; kindred; loss of function mutation; mortality; mouse model; mutant; next generation; novel; research study; telomerase reverse transcriptase; telomere; tool; tumor; tumor progression

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. PUBLIC HEALTH RELEVANCE: This proposal aims to understand the genetics that predispose to myelodysplastic syndromes and acute myeloid malignancies. Both disorders account for as many as 20,000 deaths in the United States alone and treatment options are limited and toxic. Our goal is to improve the understanding of the inherited factors that predispose to these disorders with aging with the goal of improving their prevention and treatment.

描述（由申请人提供）：端粒对于维持基因组完整性至关重要。兴奋性脑膜炎（DC）是一种癌症综合征，其特征是短端粒。受影响的患者患有血液学恶性肿瘤的风险增加，特别是骨髓增生性综合征（MDS）和急性骨髓性白血病（AML）。虽然DC是遗传性的孟德尔疾病，但端粒酶和端粒成分的种系突变仅在三分之二的家庭中被识别，在其余病例中留下了因果突变。 DC基因中的突变也是MDS和AML家族子集的继承的基础。这一事实以及MDS-AML患者的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亲密的作用。该项目研究了与理解MDS-AML发病机理的DC遗传学和生物学的两个方面。我们旨在通过研究我们已建立的注册表中的遗传未表征的DC家族来确定对端粒维持至关重要的新基因。鉴于在小型犬类中的传统链接方法的已知局限性，我们编制的同类人群为应用基因发现目的应用下一代测序技术提供了理想的设置。在AIM 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。这种鼠模型独特地概括了人类端粒长度动力学。 DC中提出的研究对于理解MDS-AML的生物学具有特殊意义，因为DC患者中发现的端粒缺陷被普遍衰老，并且尚不清楚MDS-AML越来越多的生物学。从广义上讲，它们对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影响。 公共卫生相关性：该提案旨在了解容易发生骨髓增生综合征和急性髓样恶性肿瘤的遗传学。仅在美国，这两种疾病就会造成多达20,000人死亡，治疗方案有限且有毒。我们的目标是提高人们对这些疾病的遗传因素的理解，以改善其预防和治疗。