Novel SET Antagonists for the Treatment of Chronic Myelogenous Leukemia

PROJECT SUMMARY Prenatal alcohol exposure is the leading preventable cause of birth defects in the United States, producing an array of neurological, behavioral and physical abnormalities collectively known as fetal alcohol spectrum disorders (FASD). Earlyintervention and treatment programs have been shown to reduce some of the long-term adverse effects, but this is dependent on identifying children at risk of fetal damage which is not detected in most cases. Many children affected by FASD do not exhibit obvious physical indications of prenatal alcohol-associated birth defects, creating challenges in making timely and accurate diagnoses. There is a critical need for development of biomarkers that can detect babies heavily exposed to alcohol throughout pregnancy, particularly during the first trimester when the fetal brain is most vulnerable to teratogens, to predict those at risk for developing the neurobehavioral and developmental disabilities associated with FASD. Prenatal alcohol exposure has been shown to alter DNA methylation patterns of genes known to play important roles in development and contribute to abnormal embryonic development, suggesting that alcohol-associated alterations in DNA methylation profiles, identified from neonatal blood spot samples, could be used as an alcohol biomarker in neonates. Coupling the technology United States Drug Testing Laboratories has developed for detection of the direct alcohol biomarker phosphatidylethanol (PEth) in blood spots with screening epigenetic changes associated with prenatal alcohol exposure provides an innovative approach to examine novel biological markers of alcohol exposure occurring throughout pregnancy that may be predictive of fetal damage. The objective of this Phase I project is to determine thefeasibility of using neonatal blood spots to screen alcohol-induced DNA methylation alterations and establish whether these epigenetic modifications correlate with detection of PEth. The selection of candidate regions of differential methylation will be determined by whole-genome methylation scanning of DNA from neonatal blood spot samples collected from infants with known exposure to alcohol in utero and comparing them with non- exposed controls. If prenatal alcohol exposure is significantly associated with a defined set of differentially methylated DNA sites, the feasibility of using epigenetic markers to detect newborns at risk of fetal damage will have been established and these epigenetic patterns could be further examined as possible predictive biomarkers of FASD. Development and implementation of a quantitative DNA methylation screening assay, to analyze sites of differential methylation identified in this Phase I study, would be the goal of a Phase II study. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: More than 80,000 babies born in the United States each year are at high risk for alcohol- induced birth defects, making prenatal alcohol exposure the foremost preventable source of birth defects. Early intervention and treatment programs have been shown to reduce some of the long-term adverse effects, but this is dependent on identifying children at risk of fetal alcohol damage which is not possible in most cases. This project will establish the feasibility of using epigenetic markers, identified from neonatal blood spot samples, to detect newborns at risk of fetal damage associated with excessive prenatal alcohol exposure.