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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

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十年内患上克隆性疾病，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会患上克隆性疾病。申请人的实验室和其他中心最近的工作得出这样的结论：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持续干细胞损伤的背景下产生的。去年，两位申请人各自独立开发了范可尼贫血克隆进化的独特小鼠模型。申请人在此提出使用这些模型来鉴定参与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，当与我们最近完成的人类骨髓转录组研究相结合时，不仅证实了这种疾病中克隆选择的适应性，而且还产生了常见的候选基因，即其中之一的潜力初步研究已确定其（HoxA9）可促进适应细胞的克隆选择。第二个基因家族有可能解释 FA 中 MDS 特征的随机非整倍性的分子基础。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) 和已克隆进化的 FA 细胞 (FACL)。公共健康相关性：本申请旨在确定骨髓恶性肿瘤和再生障碍性贫血发生的分子机制。从该应用中获得的信息可能会为骨髓增生异常和急性髓性白血病的治疗提供见解。这些是造血系统恶性肿瘤，对成人、尤其是老年人以及患有范可尼贫血遗传性疾病的儿童来说很重要。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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
影响因子：
0
作者：
Nalepa G;Clapp DW
通讯作者：
Clapp DW

DOI：
10.1111/hepr.12043
发表时间：
2013-09
期刊：
Hepatology research : the official journal of the Japan Society of Hepatology
影响因子：
0
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