Molecular Studies of Bone Marrow Failure

骨髓衰竭的分子研究

• 批准号: 6943092
• 负责人: Monica Bessler
• 金额: $ 51.32万
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6943092
• 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）：我们的实验室长期以来对再生障碍性贫血和其他形式的骨髓衰竭（BMF）的分子发病机制感兴趣。在儿童中，大约 25% 的 BMF 病例是遗传性的，而在成人中，这一比例甚至更低；大多数儿童和成人 BMF 病例被归类为特发性。患有遗传性 BMF 的患者容易罹患骨髓增生异常综合征 (MDS)、白血病、鳞状细胞癌和其他形式的癌症。我们实验室最近发现患有常染色体显性先天性角化不良 (DKC)（一种与癌症易感性相关的遗传性 BMF）的个体，编码端粒酶 RNA 亚基 (hTERC) 的基因存在突变。常染色体显性 DKC 患者的临床症状通常较轻微且容易被忽视。基于这一观察，我们推测 hTERC 突变可能是导致大量 BMF 病例的原因，包括目前归类为特发性的病例。此外，由于已观察到各种形式的 BMF 患者的骨髓细胞具有相对较短的端粒，因此我们推测造血干细胞中端粒过度缩短可能在 BMF 的发病机制中发挥核心作用，并导致基因组不稳定性增加，从而导致癌症的发展。为了检验这些假设，将邀请在华盛顿大学或确定的合作机构诊断或治疗 BMF 的未经选择的儿童和成人队列参加拟议的研究。同样，将从国际再生障碍性贫血和骨髓增生异常协会和其他国际骨髓衰竭登记处招募选定的患者队列。获得知情同意后，将从外周血细胞或皮肤活检中分离出的 DNA 进行 hTERC 基因突变和端粒长度/完整性研究。将使用标准化表格和程序获得每个参与者的详细临床和家族史信息。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、外显率和表达能力； 3) 研究 BMF 的发生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 的发病机制提供新的革命性见解。结果可能表明 hTERC 基因的遗传分析应该成为所有诊断为 BMF 的患者的常规预后测试。 hTERC 基因突变临床后果的表征可能对 hTERC 基因突变导致的 BMF 患者及其家庭成员的临床管理产生直接影响。拟议的研究还将增加对功能失调的端粒在人类疾病中的作用的了解，包括肿瘤发生和进展中的分子遗传途径、它们在退行性疾病和衰老中的作用。