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

• 批准号: 8536292
• 负责人: EDWARD PAUL HASTY
• 金额: $ 32.77万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 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/8536292
• 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' 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

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.

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，可进展为急性髓性白血病（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小于5年）。然而，DNA损伤和突变似乎在造血干细胞（HSC）中的起始缺陷中起关键作用。作为支持，患有某些DNA修复缺陷综合征（包括范可尼贫血（FA）和布鲁姆综合征（BS））的人表现出MDS。有趣的是，FA和BS是机械相关的，因为BS蛋白与FA途径中的蛋白质相关联，并且因为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损伤剂似乎使人易患MDS/AML，包括？辐射和苯。这两种药物都会导致染色体异常和HR修复？辐射诱发的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而使MDS/AML进展。因此，DNA损伤和DNA修复似乎是MDS/AML的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是一种转录辅激活因子，Crebbp缺陷小鼠总是随着年龄的增长而发展为MDS，通常进展为AML。重要的是，这些老鼠有修复缺陷吗？辐射诱导的DNA断裂并在胎儿肝细胞中表现出升高的突变水平。因此，Rebel博士对Crebbp缺陷小鼠的分析支持了对患者的观察，即DNA损伤和DNA修复缺陷是MDS/AML的致病因素。因此，假设是，功能齐全的HR对于抑制MDS/AML以应对导致DSB的基因毒素至关重要，而NHEJ产生导致MDS/AML的染色体易位。两个具体的目标是解决的假设。将研究Crebbp缺陷小鼠胚胎干细胞（ES细胞）（特异性目标1）和小鼠（目标2）修复？辐射和苯诱导的DNA损伤以及MDS的发展和向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，这些遗传毒素对各种骨髓细胞（包括HSC）的影响以及暴露的脆弱时间（胚胎发育与成人）。因此，本提案的结果将阐明MDS/AML的病理生物学。