Molecular Genetic Investigation of Pediatric Myelodysplastic Syndrome

描述(申请人提供)：儿童骨髓增生异常综合征(MDS)是一组不同类型的克隆性干细胞疾病，特征是不同程度的细胞减少，以及无效和发育不良的造血。MDS可分为无明显病因的原发MDS和继发于先天性或获得性骨髓衰竭(BMF)或细胞毒治疗的继发性MDS。对导致儿童MDS的启动事件知之甚少。因此，目前还没有针对性的治疗方法，而造血干细胞移植仍然是唯一的治疗选择。不同的临床和实验室表现，以及临床上注释良好的患者样本和体内模型的有限可用性，对研究该病和识别儿科MDS特有的基因改变构成了重大障碍。因此，儿科MDS在很大程度上仍按形态和细胞遗传学标准进行分类，对于分子基础提供的线索很少。在过去的18个月里，我们开发了第一个全国性的综合性儿科MDS和BMF疾病患者登记和组织储存库，目前涉及3个机构，并且还在继续增长。除了3个独特的儿童MDS家系的生物材料外，该登记中心还收集了60名个体患者的样本。这些样本构成了我们第一次基因组测序分析的基础，为未来的实验收集初步数据，并代表了这个注册表在阐明与MDS相关的致病突变方面的力量。我们独特的调查团队将利用注册和催化我们的努力，以确定儿科MDS的基本基础。该团队包括David Williams(临床/转化性血液学)、Mark Fleming(儿科血液病理学/血液学遗传学)、Benjamin Ebert(成人MDS的高通量基因组技术)和Kyriacos Markinanos(基因连锁分析)。我们将进行初步研究，以论证可行性，并生成基因组数据，为未来国家层面的假设驱动的翻译和临床研究提供基础。 公共卫生相关性：儿童MDS的潜在遗传学和病理生理学还知之甚少。通过利用几个特征良好的遗传性MDS家系，我们将致力于确定这种疾病的遗传基础。所获得的结果不仅有望为儿童患者的生物学提供关键的见解，而且可能会增加对成人MDS遗传学的了解。

DESCRIPTION (provided by applicant): Pediatric Myelodysplastic Syndrome (MDS) is a heterogeneous group of clonal stem cell disorders characterized by varying degrees of cytopenias, and ineffective and dysplastic hematopoiesis. MDS can be classified as primary de novo MDS with no apparent underlying cause and secondary MDS following congenital or acquired bone marrow failure (BMF) disorders or cytotoxic therapies. Little is known about initiating events leading to pediatric MDS. As a result, no targeted therapies exist and hematopoietic stem cell transplantation remains the only therapeutic option. The heterogeneous clinical and laboratory presentation and limited availability of clinically well-annotated patient samples and in vivo models have posed significant obstacles to study the disease and to identify genetic alterations unique to pediatric MDS. Therefore pediatric MDS remains largely classified by morphologic and cytogenetic criteria that provide few clues as to the molecular basis. Over the last 18 months, we have developed the first nationwide comprehensive Pediatric MDS and BMF Disorder Patient Registry and Tissue Repository now involving 3 institutions and continuing to grow. The registry has collected samples from > 60 individual patients in addition to biological material from 3 unique kindreds with pediatric MDS. These samples form the basis for our first genomic sequencing analysis to gather preliminary data for future experiments and represent the power of this registry to elucidate pathogenic mutations associated with MDS. Our unique team of investigators will exploit the registry and catalyze our efforts to determine the fundamental underpinnings of pediatric MDS. The team includes David Williams (clinical/translational hematology), Mark Fleming (pediatric hematopathology /hematological genetics), Benjamin Ebert (high throughput genomic technologies in adult MDS) and Kyriacos Markinanos (genetic linkage analysis). We will undertake preliminary studies to demonstrate feasibility, and generate genomic data that will provide the basis for future hypothesis-driven translational and clinical research studies on a national level. PUBLIC HEALTH RELEVANCE: The underlying genetics and pathophysiology of pediatric MDS is poorly understood. By exploiting several well-characterized families with inherited MDS, we will aim to identify the genetic basis for this disorder. Results obtained not only promise to provide critical insights into the biology of pediatric patients, but will likely increase knowledg into the genetics of adult MDS.