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: 8302374
• 负责人: Grover Carlton Bagby
• 金额: $ 37.94万
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302374
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult; Aneuploidy; Aplastic Anemia; Apoptosis; Bone Marrow; Candidate Disease Gene; Cells; Characteristics; Child; Chromatin; Clonal Evolution; Complementary DNA; 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; TNF gene; 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 - 20%的获得性再生障碍性贫血幸存者在诊断后的十年内会发展为克隆性疾病，高达40%的儿童和年轻人患有遗传性骨髓衰竭综合征范可尼贫血。来自申请人的实验室和来自其他中心的最新工作得出以下结论：再生障碍状态下的克隆进化是在通过克隆选择和适应过程进行的干细胞损伤的背景下产生的。在过去的一年中，两位申请人各自独立地开发了范可尼贫血中克隆进化的独特小鼠模型。申请人在本文中提出使用这些模型来鉴定涉及FA干细胞克隆进化的最早分子事件。这些模型为全基因组表达分析提供了材料，当与我们最近完成的对人骨髓转录组的研究相结合时，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，其中之一（HoxA 9）促进适应细胞的克隆选择的潜力已经在初步研究中建立。第二个基因家族有可能解释FA中MDS特征性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风险患者克隆进化的策略。我们将使用未经历克隆进化（FAAPL）的鼠和人FA细胞和已克隆进化（FACL）的FA细胞。 公共卫生关系：本申请旨在确定髓系恶性肿瘤和再生障碍性贫血发生的分子机制。从该应用程序中获得的信息可能会为骨髓增生异常和急性髓细胞白血病的治疗提供见解。这些是造血系统恶性肿瘤，在成年人，特别是老年人以及患有称为范可尼贫血的遗传性疾病的儿童中很重要。

项目成果

Design, synthesis, and evaluation of curcumin-derived arylheptanoids for glioblastoma and neuroblastoma cytotoxicity.

姜黄素衍生的芳基类动物的设计，合成和评估，用于胶质母细胞瘤和神经母细胞瘤细胞毒性。

• DOI: 10.1016/j.bmcl.2013.09.095
• 发表时间: 2013-12-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Campos, Catherine A.;Gianino, Joseph B.;Bailey, Barbara J.;Baluyut, Mary E.;Wiek, Constanze;Hanenberg, Helmut;Shannon, Harlan E.;Pollok, Karen E.;Ashfeld, Brandon L.
• 通讯作者: Ashfeld, Brandon L.

Fanconi anemia and the cell cycle: new perspectives on aneuploidy.

• DOI: 10.12703/p6-23
• 发表时间: 2014
• 期刊: F1000prime reports
• 作者: Nalepa G;Clapp DW
• 通讯作者: Clapp DW

Living related liver transplantation in an adult patient with hepatocellular adenoma and carcinoma 13 years after bone marrow transplantation for Fanconi anemia: A case report.

• DOI: 10.1111/hepr.12043
• 发表时间: 2013-09
• 期刊: Hepatology research : the official journal of the Japan Society of Hepatology
• 作者: Colle I;Laureys G;Raevens S;Libbrecht L;Leroy JG;Reyntjens K;Geerts A;Rogiers X;Troisi RI;Hoehn H;Schindler D;Hanenberg H;De Wilde V;Van Vlierberghe H
• 通讯作者: Van Vlierberghe H

RAD51C--a new human cancer susceptibility gene for sporadic squamous cell carcinoma of the head and neck (HNSCC).

• DOI: 10.1016/j.oraloncology.2013.11.007
• 发表时间: 2014-03
• 期刊: ORAL ONCOLOGY
• 影响因子: 4.8
• 作者: Scheckenbach, Kathrin;Baldus, Stephan E.;Balz, Vera;Freund, Marcel;Pakropa, Petra;Sproll, Christoph;Schaefer, Karl-Ludwig;Wagenmann, Martin;Schipper, Joerg;Hanenberg, Helmut
• 通讯作者: Hanenberg, Helmut