Int. J. Environ. Res. Public Health 2012, 9, 1939-1953; doi:10.3390/ijerph9051939 OPEN ACCESS International Journal of Environmental Research and Public Health ISSN 1660-4601 www.mdpi.com/journal/ijerph Article The Aryl Hydrocarbon Receptor Pathway: A Key Component of the microRNA-Mediated AML Signalisome Julia E. Rager 1 and Rebecca C. Fry 1,2,* 1 Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina, 135 Dauer Drive, CB 7431, UNC, Chapel Hill, NC 27599, USA; E-Mail: jrager@live.unc.edu 2 Curriculum in Toxicology, The University of North Carolina, 135 Dauer Drive, CB 7431, UNC, Chapel Hill, NC 27599, USA * Author to whom correspondence should be addressed; E-Mail: rfry@unc.edu; Tel.: +1-919-843-6864; Fax: +1-919-843-9047. Received: 21 March 2012; in revised form: 27 April 2012 / Accepted: 8 May 2012 / Published: 18 May 2012 Abstract: Recent research has spotlighted the role of microRNAs (miRNAs) as critical epigenetic regulators of hematopoietic stem cell differentiation and leukemia development. Despite the recent advances in knowledge surrounding epigenetics and leukemia, the mechanisms underlying miRNAs’ influence on leukemia development have yet to be clearly elucidated. Our aim was to identify high ranking biological pathways altered at the gene expression level and under epigenetic control. Specifically, we set out to test the hypothesis that miRNAs dysregulated in acute myeloid leukemia (AML) converge on a common pathway that can influence signaling related to hematopoiesis and leukemia development. We identified genes altered in AML patients that are under common regulation of seven key miRNAs. By mapping these genes to a global interaction network, we identified the “AML Signalisome”. The AML Signalisome comprises 53 AML-associated molecules, and is enriched for proteins that play a role in the aryl hydrocarbon receptor (AhR) pathway, a major regulator of hematopoiesis. Furthermore, we show biological enrichment for hematopoiesis-related proteins within the AML Signalisome. These findings provide important insight into miRNA-regulated pathways in leukemia, and may help to prioritize targets for disease prevention and treatment.