Molecular Studies of Bone Marrow Failure

骨髓衰竭的分子研究

• 批准号: 6826174
• 负责人: Monica Bessler
• 金额: $ 54.98万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826174
• 关键词: RNA; aplastic anemia; biomarker; blood disorder diagnosis; bone marrow disorder; cancer risk; chemical structure function; chromosome aberrations; clinical research; disease /disorder etiology; disease /disorder onset; dyserythropoietic anemia; family genetics; gene environment interaction; gene interaction; gene mutation; genetic susceptibility; hematopoietic stem cells; human genetic material tag; human subject; molecular pathology; neoplasm /cancer genetics; nucleic acid structure; patient oriented research; telomere

DESCRIPTION (provided by applicant): Our laboratory has a longstanding interest in the molecular pathogenesis of aplastic anemia and other forms of bone marrow failure (BMF). In children about 25% of cases of BMF are inherited, while in adults the percentage is even lower; most cases of BMF in children and adults are classified as idiopathic. Patients with inherited forms of BMF have a predisposition to develop myelodysplastic syndrome (MDS), leukemia, squamous cell carcinoma, and other forms of cancer. Our laboratory was involved in the recent discovery that individuals with autosomal dominant dyskeratosis congenita (DKC), an inherited form of BMF associated with cancer susceptibility, have mutations in the gene encoding the telomerase RNA subunit (hTERC). Clinical signs in patients with autosomal dominant DKC are often mild and are easily missed. Based on this observation we postulate that mutations in hTERC may be responsible for a significant number of cases of BMF, including cases currently classified as idiopathic. Moreover, because bone marrow cells from patients with various forms of BMF have been observed to have relatively short telomeres, we hypothesize that excessive telomere shortening in hematopoietic stem cells may play a central role in the pathogenesis of BMF and cause increased genomic instability that predisposes to the development of cancer. To test these hypotheses, an unselected cohort of children and adults diagnosed or treated for BMF at Washington University or at identified collaborating institutions will be invited to participate in the proposed study. Similarly, a selected patient cohort will be enrolled from the International Aplastic Anemia and Myelodysplasia Society and other international bone marrow failure registries. After obtaining informed consent, DNA isolated from peripheral blood cells or from a skin biopsy will be examined for mutations in the hTERC gene and for telomere length/integrity studies. Detailed clinical and family history information will be obtained for each participant using standardized forms and procedures. There are several goals of this study: 1) to determine the frequency of hTERC gene mutations; 2) to delineate the heritability, penetrance and expressivity of hTERC gene mutations; and 3) to investigate whether the onset and severity of BMF correlates with telomere length and integrity. The proposed studies will help to elucidate the clinical consequences of mutations in the hTERC gene and provide new revolutionary insights into the pathogenesis of BMF. The results may indicate genetic analysis of the hTERC gene should become a routine prognostic test for all patients diagnosed with BMF. The characterization of the clinical consequences of hTERC gene mutations is likely to have a direct impact on the clinical management of patients with BMF due to hTERC gene mutations and their family members. The proposed studies will also increase the knowledge of the role of dysfunctional telomeres in human disease, including the molecular genetic pathways in tumor initiation and progression, their role in degenerative diseases, and in aging.

描述（由申请人提供）：我们的实验室对性障碍性贫血的分子发病机理和其他形式的骨髓衰竭（BMF）具有长期的兴趣。在儿童中，大约25％的BMF病例是继承的，而在成年人中，百分比较低。儿童和成人中BMF的大多数病例被归类为特发性。 BMF遗传形式的患者具有发展骨髓增生综合征（MDS），白血病，鳞状细胞癌和其他形式的癌症的倾向。我们的实验室参与了最近的发现，即常染色体显性异常性疾病的患者（DKC）是一种与癌症易感性相关的遗传形式的BMF形式，在编码端粒酶RNA亚基（HTERC）的基因中具有突变。常染色体显性DKC患者的临床体征通常很温和，很容易错过。基于这一观察结果，我们假设HTERC中的突变可能是大量BMF病例的原因，包括当前归类为特发性的病例。此外，由于已经观察到来自不同形式BMF患者的骨髓细胞的端粒相对较短，因此我们假设造血干细胞中过度的端粒缩短可能在BMF的发病机理中起着核心作用，并导致基因组不稳定性增加，使癌症发育易感性。为了检验这些假设，将邀请在华盛顿大学诊断或接受BMF或在确定的合作机构中被诊断或治疗的儿童和成人队列参加。同样，一名选定的患者队列将从国际性障碍性贫血和骨髓增生社会和其他国际骨髓衰竭登记处入学。在获得知情同意书后，将检查从外周血细胞或皮肤活检中分离出的DNA，以了解HTERC基因中的突变以及端粒长度/完整性研究。将使用标准化表格和程序为每个参与者获得详细的临床和家族史信息。这项研究有几个目标：1）确定HTERC基因突变的频率； 2）描述HTERC基因突变的遗传力，外观和表现力； 3）研究BMF的发作和严重程度是否与端粒长度和完整性相关。拟议的研究将有助于阐明HTERC基因突变的临床后果，并为BMF发病提供新的革命性见解。结果可能表明对HTERC基因的遗传分析应成为所有被诊断为BMF的患者的常规预后测试。 HTERC基因突变的临床后果的表征可能会直接影响由于HTERC基因突变及其家人引起的BMF患者的临床管理。拟议的研究还将增加对端粒功能失调在人类疾病中的作用的知识，包括肿瘤启动和进展中的分子遗传途径，它们在退化性疾病中的作用以及在衰老中的作用。