Genomics of myelodysplastic syndromes

骨髓增生异常综合征的基因组学

• 批准号: 7685736
• 负责人: TIMOTHY A GRAUBERT
• 金额: $ 1.99万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7685736
• 关键词: Acute Myelocytic Leukemia; Adverse event; Affect; Alkylating Agents; Alkylating Antineoplastic Agents; Alleles; Bacterial Artificial Chromosomes; Biological; Biological Assay; Bone Marrow; Bone Marrow Cells; Candidate Disease Gene; Cells; Chromosomal Duplication; Chromosomal Gain; Chromosome abnormality; Clinical; Clonal Expansion; Collaborations; Complement; Custom; Cytogenetic Analysis; Cytogenetics; DNA; DNA Resequencing; DNA Sequence; Data; Databases; Deposition; Development; Disease; Dysmyelopoietic Syndromes; Exposure to; FLT3 gene; Gene Mutation; Genes; Genetic; Genetic Polymorphism; Genome; Genomics; Goals; Hand; Hematopoiesis; Hematopoietic; Homologous Gene; Human; Human Genome; In Vitro; Institution; Laboratories; Modeling; Mus; Mutate; Mutation; Nitrosourea Compounds; Numbers; Outcome; Pathogenesis; Patients; Penetrance; Point Mutation; Receptor Tyrosine Kinase Gene; Recurrence; Research Personnel; Resolution; Resources; SWR/J Mouse; Sampling; Skin; Standards of Weights and Measures; Structure; Techniques; Universities; Validation; Washington; base; comparative genomic hybridization; cytopenia; day; design; follow-up; genome sequencing; improved; in vivo; mouse model; novel; outcome forecast; programs; tumor

The myelodysplastic syndromes (MDS) are a heterogenous group of disorders characterized by clonal expansion of hematopoietic cells. Cytopenias and transformation to acute myeloid leukemia are important sequelae of MDS. The genetic basis of these disorders is poorly understood. The longterm goal of this project is to identify and characterize new mutations that are important for MDS initiation and progression. We propose to conduct a large-scale study of the genomics of MDS, utilizing high-throughput resequencing and array-based comparative genomic hybridization to identify novel genetic changes in samples from patients with MDS. We have also produced a unique mouse model of alkylator-induced MDS that will complement the search for mutations that are important for human MDS. We have several key resources available that make this project feasible, including a bank of matched tumor and germline (skin) samples from MDS patients, a close collaboration with the Washington University Genome Sequencing Center, prevalidated primers for all the genes selected for resequencing, and custom-produced bacterial artificial chromosome (BAG) arrays representing the complete tiling paths for the mouse and human genomes. With these resources in hand, we propose the following specific aims: Specific Aim 1: We will utilize highthroughput DMA sequencing and comparative genomic hybridization to identify genetic changes in samples from patients with myelodysplastic syndromes. Specific Aim 2: We will utilize a mouse model of t-MDS to identify and characterize novel mutations associated with the development of myelodysplastic syndromes. These Aims are complementary and are structured to provide independent validation for the mutations we find. Although the goals of this project are primarily mutation discovery, we will utilize standard in vitro and in vivo assays to confirm the biological consequences of the mutations we discover. All genetic data that we obtain in these studies will be deposited in publicly accessible databases in a format that will be useful to other investigators. Lay Audience Summary: We propose to use several unique resources available at our institution to discover new information about the genetic basis of the myelodysplastic syndromes. These findings should improve our ability to predict the prognosis of patients with MDS and provide a rational basis for designing specific therapies that are more effective and less toxic.

骨髓增生异常综合征（MDS）是一种以造血细胞克隆扩增为特征的异质性疾病。细胞减少和向急性髓性白血病的转化是MDS的重要后遗症。这些疾病的遗传基础尚不清楚。该项目的长期目标是确定和表征对MDS的发生和进展至关重要的新突变。我们建议对MDS进行大规模的基因组学研究，利用高通量重测序和基于阵列的比较基因组杂交来鉴定MDS患者样本中的新的遗传变化。我们还建立了一种独特的烷基化剂诱导的MDS小鼠模型，该模型将补充对人类MDS重要突变的研究。我们有几个关键资源可以使这个项目可行，包括一个匹配的肿瘤和种系（皮肤）样本库，与华盛顿大学基因组测序中心的密切合作，为重测序选择的所有基因预先验证引物，以及定制的细菌人工染色体（BAG）阵列，代表小鼠和人类基因组的完整铺层路径。有了这些资源，我们提出以下具体目标：具体目标1：我们将利用高通量DMA测序和比较基因组杂交来鉴定骨髓增生异常综合征患者样本的遗传变化。具体目标2：我们将利用t-MDS小鼠模型来识别和表征与骨髓增生异常综合征发展相关的新突变。这些目标是互补的，并为我们发现的突变提供独立的验证。虽然这个项目的目标主要是发现突变，但我们将利用标准的体外和体内试验来确认我们发现的突变的生物学后果。我们在这些研究中获得的所有遗传数据将以对其他研究人员有用的格式存储在可公开访问的数据库中。摘要：我们建议利用我们机构的一些独特资源来发现关于骨髓增生异常综合征遗传基础的新信息。这些发现将提高我们预测MDS患者预后的能力，并为设计更有效、毒性更小的特异性治疗方法提供合理依据。