Fanconi Anemia stem cells allow molecular characterization of acute leukemia

范可尼贫血干细胞可对急性白血病进行分子表征

• 批准号: 7692961
• 负责人: Grover Carlton Bagby
• 金额: $ 39.33万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7692961
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult; Aneuploidy; Aplastic Anemia; Apoptosis; Bone Marrow; Candidate Disease Gene; Cells; Characteristics; Child; Chromatin; Clonal Evolution; DNA Damage; Data; Defect; Development; Diagnosis; Disease; Elderly; Epigenetic Process; Event; Evolution; Failure; Family; Fanconi' s Anemia; Gene Expression Profile; Gene Family; Genes; Genetic; Goals; HOXA9 gene; Hematopoietic; Hematopoietic stem cells; Hereditary Disease; Human; Hypersensitivity; In Vitro; Inherited; Knock-out; Knowledge; Laboratories; Learning; Marrow; Methods; Mitotic/Spindle Checkpoint; Modeling; Molecular; Mus; Myeloproliferative disease; Nature; Pancytopenia; Pathogenesis; Pathway interactions; Patients; Phenotype; Point Mutation; Positioning Attribute; Prevention strategy; Process; Proteins; Research Personnel; Role; Signal Transduction; Stem cells; Survivors; Syndrome; Testing; Work; base; cell injury; cytokine; genome-wide; genotoxicity; high risk; in vivo; insight; interest; leukemogenesis; mutant; overexpression; public health relevance; response; young adult

DESCRIPTION (provided by applicant): From 10 to 20% of acquired aplastic anemia survivors will develop a clonal disease within the decade following their diagnosis as will up to 40% of children and young adults with the inherited bone marrow failure syndrome Fanconi anemia. Recent work from the laboratories of the applicants and from other centers leads to the conclusion that clonal evolution in aplastic states arises in the context of ongoing stem cell damage through a process of clonal selection and adaptation. In the past year the two applicants have each independently developed a unique murine model of clonal evolution in Fanconi anemia. The applicants propose herein to use these models to identify the earliest molecular events involved in clonal evolution of FA stem cells. These models provided material for genome wide expression analyses which, when combined with our recently completed studies on the human bone marrow transcriptome, have not only confirmed the adaptive nature of clonal selection in this disease but have yielded common candidate genes, the potential of one of which (HoxA9) to facilitate clonal selection of adapted cells has been established in preliminary studies. A second family of genes has potential to explain the molecular underpinnings of the random aneuploidy that is characteristic of MDS in FA. Collectively, our goals are to identify genetic and epigenetic causes of clonal evolution in vitro and in vivo. We anticipate that by doing so, we can use the knowledge to develop strategies for prevention of clonal evolution in patients at high risk. We will use murine and human FA cells that have not undergone clonal evolution (FAAPL) and FA cells that have clonally evolved (FACL). PUBLIC HEALTH RELEVANCE: This application seeks to identify molecular mechanisms that underlie the development of myeloid malignancies and aplastic anemia. Information learned from this application may provide insights into the treatment of myelodys plasia and acute myelogenous leukemia. These are hematopoietic malignances that are important in adults and particularly the elderly as well as in children with a genetic disorder called Fanconi Anemia.

描述（由申请人提供）：10%至20%的获得性再生障碍性贫血幸存者将在诊断后的十年内发展为克隆性疾病，高达40%的患有遗传性骨髓衰竭综合征范可尼贫血的儿童和年轻人将发展为克隆性疾病。申请者的实验室和其他中心最近的工作得出结论，再生状态的克隆进化是在干细胞持续损伤的背景下通过克隆选择和适应过程产生的。在过去的一年里，两位申请者各自独立开发了一种独特的范可尼贫血克隆进化的小鼠模型。申请人在此建议使用这些模型来确定FA干细胞克隆进化中涉及的最早分子事件。这些模型为基因组全表达分析提供了材料，结合我们最近完成的人类骨髓转录组研究，不仅证实了这种疾病中克隆选择的适应性，而且产生了共同的候选基因，其中一个（HoxA9）促进适应细胞克隆选择的潜力已在初步研究中确立。第二个基因家族有可能解释FA中MDS特征的随机非整倍体的分子基础。总的来说，我们的目标是确定体外和体内克隆进化的遗传和表观遗传原因。我们预计，通过这样做，我们可以利用这些知识来制定预防高危患者克隆进化的策略。我们将使用未经历克隆进化的小鼠和人FA细胞（FAAPL）和已经克隆进化的FA细胞（FACL）。