Fanconi Anemia stem cells allow molecular characterization of acute leukemia

描述(申请人提供)：约10%至20%的获得性再生障碍性贫血幸存者将在确诊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也将如此。申请者的实验室和其他中心最近的工作得出结论，再生障碍性疾病的克隆进化是在干细胞通过克隆选择和适应过程持续受损的背景下产生的。在过去的一年里，这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小鼠模型。申请人在此建议使用这些模型来确定涉及FA干细胞克隆进化的最早的分子事件。这些模型为全基因组表达分析提供了材料，与我们最近完成的对人类骨髓转录组的研究相结合，不仅证实了克隆选择在这种疾病中的适应性，而且产生了共同的候选基因，其中之一(HoxA9)促进适应细胞克隆选择的潜力已在初步研究中建立。第二个基因家族有可能解释随机非整倍体的分子基础，这是FA中MDS的特征。总的来说，我们的目标是确定在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类FA细胞(FAAPL)和已经克隆进化的FA细胞(FACL)。 公共卫生相关性：这项应用寻求确定髓系恶性肿瘤和再生障碍性贫血发生的分子机制。从这一应用中了解到的信息可能为骨髓增生异常和急性髓系白血病的治疗提供洞察力。这些是血液系统的恶性肿瘤，对成人，特别是老年人，以及患有范可尼贫血的儿童都很重要。

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.