Study DNA repair in preventing MDS and AML after radiation and benzene exposure

研究 DNA 修复在辐射和苯暴露后预防 MDS 和 AML 的作用

基本信息

批准号：
8390283
负责人：
EDWARD PAUL HASTY
金额：
$ 33.44万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8390283
关键词：
Abbreviations Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Address Adult Age Apoptosis Benzene Benzene Exposure Binding Proteins Blood Cells Bloom Syndrome Bloom syndrome protein Bone Marrow Bone Marrow Cells Bone Marrow Diseases Camptothecin Cells Chromosomal Stability Chromosomal translocation Chromosome abnormality Collaborations Cyclic AMP DNA DNA Damage DNA Double Strand Break DNA Repair DNA lesion Defect Development Diagnosis Disease Disease Progression Double Strand Break Repair Dysmyelopoietic Syndromes Elements Embryo Embryonic Development Environmental Risk Factor Etiology Event Exhibits Exons Exposure to Failure Fanconi&apos s Anemia Fetal Development Fetal Liver Gene Mutation Genes Genetic Genetic screening method Genomic Instability Goals Health Sciences Hematopoietic stem cells Hepatocyte Human In Vitro Lead Maintenance Mitomycins Modeling Mus Mutagens Mutant Strains Mice Mutate Mutation Nature Pathway interactions Patients Play Predisposition Proteins Radiation Radiation Induced DNA Damage Radiation induced double strand break Reactive Oxygen Species Resolution Role Sister Chromatid Exchange Staging Syndrome Testing Time Transcription Coactivator Whole-Body Irradiation XRCC5 gene embryonic stem cell helicase homologous recombination interest leukemia mouse model mutant p-Benzoquinones para-benzoquinone prevent recombinational repair repaired response stem tissue culture

项目摘要

DESCRIPTION (provided by applicant): Myelodysplastic syndrome (MDS) is a group of disorders characterized by dysfunctional blood cells that can progress to acute myeloid leukemia (AML). At this time the etiology of MDS development and progression to AML is not understood and there is no cure (median survival at time of diagnosis is less than 5 years). Yet, DNA damage and mutations appear to play a key role with the initiating defect in a hematopoietic stem cell (HSC). In support, people with certain DNA repair defective syndromes including Fanconi anemia (FA) and Bloom syndrome (BS) exhibit MDS. Interestingly, FA and BS are mechanistically related since the BS protein associates with proteins in the FA pathway and since both influence the repair of DNA double-strand breaks (DSBs) through the homologous recombination (HR) pathway. In addition, some DNA damaging agents appear to predispose people to MDS/AML including ?-radiation and benzene. Both of these agents cause chromosomal abnormalities and HR repairs ?-radiation-induced DSBs. Furthermore, another DSB repair pathway, nonhomologous end joining (NHEJ) may enable the progression of MDS/AML by facilitating chromosomal translocations. Thus, DNA damage and DNA repair appear to be integral factors in the etiology of MDS/AML. This proposal is a collaboration between two labs with expertise in MDS/AML, (Dr. Rebel's lab) and DNA damage/repair (Dr. Hasty's lab). Dr. Rebel has studied MDS/AML in a Crebbp-deficient mouse model. Crebbp is a transcriptional coactivator and Crebbp-deficient mice invariably develop MDS with age that often progress to AML. Importantly, these mice are defective for repairing ?-radiation-induced DNA breaks and exhibit elevated mutation levels in fetal liver cells. Thus, Dr. Rebel's analysis on Crebbp-deficient mice support observations made on patients that DNA damage and defects in DNA repair are causal factors in MDS/AML. Therefore, the hypothesis is that fully functional HR is critical for suppressing MDS/AML in response to genotoxins that cause DSBs while NHEJ generates chromosomal translocations that cause MDS/AML. Two specific aims are presented to address the hypothesis. Crebbp-deficient mouse embryonic stem (ES) cells (Specific Aim 1) and mice (aim 2) will be investigated for the dynamics of repairing ?-radiation- and benzene-induced DNA lesions and the development of MDS and progression to AML. It is anticipated that this will lead to a better understanding of the role that DNA damage/repair plays in disease progression, the impact these genotoxins have on a variety of bone marrow cells including HSCs and vulnerable times of exposure (embryonic development vs. adult). Thus, results from this proposal will elucidate the pathobiology of MDS/AML. PUBLIC HEALTH RELEVANCE: Myelodysplastic syndrome (MDS) is a pre-leukemic bone marrow disorder that may progress to acute myeloid leukemia (AML). Genetic instability likely facilitates each stage of this disease with the initiating event occurring in a HSC; therefore, environmental genotoxins and defective DNA repair that are known to cause genetic instability could enable MDS/AML. The goal of this proposal is to elucidate the role DNA repair and genomic instability play in the etiology of this poorly understood disease.

描述（由申请人提供）：骨髓增生异常综合征（MDS）是一组以血细胞功能障碍为特征的疾病，可进展为急性髓系白血病（AML）。目前，MDS 发展和进展为 AML 的病因尚不清楚，也无法治愈（诊断时的中位生存期不到 5 年）。然而，DNA 损伤和突变似乎在造血干细胞 (HSC) 的起始缺陷中发挥着关键作用。作为支持，患有某些 DNA 修复缺陷综合征（包括范可尼贫血 (FA) 和布卢姆综合征 (BS)）的人会表现出 MDS。有趣的是，FA 和 BS 在机制上是相关的，因为 BS 蛋白与 FA 途径中的蛋白质结合，并且两者都通过同源重组 (HR) 途径影响 DNA 双链断裂 (DSB) 的修复。此外，一些 DNA 损伤剂似乎会使人容易患 MDS/AML，包括 β-辐射和苯。这两种药物都会导致染色体异常和 HR 修复 β 辐射诱导的 DSB。此外，另一种 DSB 修复途径，非同源末端连接 (NHEJ) 可能通过促进染色体易位来促进 MDS/AML 的进展。因此，DNA 损伤和 DNA 修复似乎是 MDS/AML 病因学中不可或缺的因素。该提案是两个在 MDS/AML（Rebel 博士的实验室）和 DNA 损伤/修复（Hasty 博士的实验室）方面拥有专业知识的实验室之间的合作。 Rebel 博士在 Crebbp 缺陷小鼠模型中研究了 MDS/AML。 Crebbp 是一种转录共激活因子，Crebbp 缺陷的小鼠总是会随着年龄的增长而患上 MDS，并常常进展为 AML。重要的是，这些小鼠在修复β-辐射诱导的DNA断裂方面存在缺陷，并且胎儿肝细胞中的突变水平升高。因此，Rebel 博士对 Crebbp 缺陷小鼠的分析支持了对患者的观察结果，即 DNA 损伤和 DNA 修复缺陷是 MDS/AML 的致病因素。因此，假设功能齐全的 HR 对于抑制 MDS/AML 至关重要，以响应引起 DSB 的基因毒素，而 NHEJ 会产生导致 MDS/AML 的染色体易位。提出了两个具体目标来解决该假设。将研究 Crebbp 缺陷型小鼠胚胎干 (ES) 细胞（具体目标 1）和小鼠（目标 2）修复 β-辐射和苯诱导的 DNA 损伤的动态以及 MDS 的发展和 AML 的进展。预计这将有助于更好地了解 DNA 损伤/修复在疾病进展中的作用、这些基因毒素对包括 HSC 在内的各种骨髓细胞的影响以及暴露的脆弱时间（胚胎发育与成人）。因此，该提案的结果将阐明 MDS/AML 的病理学。公共卫生相关性：骨髓增生异常综合征 (MDS) 是一种白血病前期骨髓疾病，可能进展为急性髓系白血病 (AML)。遗传不稳定性可能会促进这种疾病的各个阶段，起始事件发生在 HSC 中；因此，已知会导致遗传不稳定的环境基因毒素和有缺陷的 DNA 修复可能会导致 MDS/AML。该提案的目的是阐明 DNA 修复和基因组不稳定性在这种人们知之甚少的疾病的病因学中所起的作用。