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.
Various lines of evidence point to a role of chemical environmental risk factors in leukemia risk. This project aims to determine a mechanism linking environmental risk factors (such as parental smoking, pesticide, PCBs, and PBDEs) and a biological imprint within leukemia cells: DNA methylation in gene promoters. We will establish the role of DNA methylation as a biomarker of early biological effect from environmental exposures as well as a precursor to leukemia, and will explore the use of these biomarkers in the early detection and prediction of leukemia using neonatal dried blood spots from the general population.
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