Project 3: Prenatal Exposure, DNA Methylation & Childhood Leukemia

项目总结(见说明)： 在细胞水平上，儿科白血病和其他癌症一样，是由遗传和表观遗传改变引起的。不同亚型的细胞遗传学异常在儿童时期已被认识多年，是白血病患者管理和最近的流行病学研究的基石。最近关于白血病表观遗传学的研究表明，包括DNA甲基化在内的改变是儿童ALL的常见和潜在的重要特征。我们和其他人的初步研究表明，白血病中的DNA甲基化事件是复杂的。一些事件反映了正常的发育表观遗传程序，因此这些事件只是反映了被转化的祖细胞群体的正常生物学。其他事件是在转换过程中获取的。有些可能是由于环境暴露和发育异常导致的早期表观遗传异常。在这个项目中，我们将尝试描述儿童白血病中的关键DNA甲基化事件，并进一步定义那些受环境影响的事件，特别是在产前。目标是开发一组与暴露和白血病相关的生物标记物，可用于未来的生物监测、风险分层和流行病学研究。我们将使用高维技术表征正常B细胞前体细胞和一系列白血病骨髓样本(n=250)的DNA甲基化模式，以确定在白血病中至关重要的DNA甲基化事件。其次，我们将利用相同的技术，使用新生儿干血斑点(DBS)DNA，在相同的250例白血病患者及其病例血中定义出生时的DNA甲基化模式。使用新的统计技术，我们将把DNA甲基化模式和单个基因与环境暴露的具体和定量数据联系起来，包括对房屋灰尘中超过120种分析物的化学分析，以及对200名受试者的白蛋白化学加合物的评估(来自项目2)。利用这些信息，我们将使用北加州儿童白血病研究的一组不同的新生儿DBS和加利福尼亚州公共卫生部的一套新卡片来验证最具信息量的(即与白血病和环境相关的)甲基化标志物的子集，并试图了解DNA甲基化在白血病相关DNA出生时基因-环境相互作用中的作用。

PROJECT SUMMARY (See instructions): At the cellular level pediatric leukemias like other cancers are caused by genetic and epigenetic alterations. Distinct subtypes of cytogenetic abnormalities have been recognized in childhood ALL for many years and are cornerstones of leukemia patient management and more recently, epidemiology studies. Recent studies on the epigenetic of leukemia suggest that alterations including DNA methylation are common and potentially important features of childhood ALL. Our preliminary studies and those of others have shown that DNA methylation events in leukemia are complex. Some events are reflective of the normal developmental epigenetic programs and therefore the events simply mirror the normal biology of the progenitor population of cells that were transformed. Other events are acquired during the transformation process. Some may arise from early epigenetic aberrations resulting from environmental exposures and developmental abnormalities. In this project we will attempt to delineate the critical DNA methylation events in pediatric leukemias and furthermore define those influenced by the environment, particularly in the prenatal period. The development of a panel of exposure- and leukemia-related biomarkers is the goal, which could be utilized in future biomonitoring, risk stratification, and epidemiology studies. We will characterize the DNA methylation pattern of normal B-cell progenitors and a series of leukemia bone marrow samples (n=250) using a high dimension technology, to define the DNA methylation events critical in leukemia. Second, we will utilize the same technology to define the DNA methylation pattern at birth on same 250 leukemia cases and their case bloods using neonatal dried blood spot (DBS) DNA. Using novel statistical techniques, we will associate DNA methylation patterns and individual genes to specific and quantitative data on environmental exposures including a chemical analysis of over 120 analytes in house dust, with repeat measurements at 150 houses, and an assessment of albumin-chemical adducts in 200 subjects (from Project 2). Using this information we will validate a subset of the most informative (ie., leukemia- and environmental-associated) methylation markers using a distinct set of neonatal DBS that are part of the Northern California Childhood Leukemia Study and a new set of cards from the California Department of Public Health, and seek to understand the role of DNA methylation in gene-environment interaction in leukemia-associated DNA methylation at birth.