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

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失调为特征的疾病，可进展为急性髓性白血病（AML）。目前MDS发展和发展为AML的病因尚不清楚，也没有治愈方法（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）的初始缺陷中起着关键作用。支持，某些DNA修复缺陷综合征，包括范可尼贫血症（FA）和布鲁姆综合征（BS）的人表现为MDS。有趣的是，FA和BS在机制上是相关的，因为BS蛋白与FA途径中的蛋白质相关，并且都通过同源重组（HR）途径影响DNA双链断裂（DSBs）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。这两种药物都会引起染色体异常和HR修复。辐射诱导双边带。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。该提案是两个具有MDS/AML专业知识的实验室（Rebel博士的实验室）和DNA损伤/修复（Hasty博士的实验室）之间的合作。Rebel博士在crebbp缺陷小鼠模型中研究MDS/AML。Crebbp是一种转录共激活因子，Crebbp缺陷小鼠总是随着年龄的增长而发展为MDS，并经常发展为AML。重要的是，这些老鼠有缺陷，无法修复？-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的病因。因此，假设功能完整的HR对于抑制基因毒素引起dsb的MDS/AML至关重要，而NHEJ产生导致MDS/AML的染色体易位。提出了两个具体的目标来解决这个假设。crebbp缺陷小鼠胚胎干（ES）细胞（Specific Aim 1）和小鼠（Aim 2）的修复动力学将被研究。-辐射和苯诱导的DNA损伤与MDS的发展和AML的进展。预计这将导致更好地理解DNA损伤/修复在疾病进展中的作用，这些基因毒素对包括造血干细胞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，本研究结果将阐明MDS/AML的病理生物学。

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.