Int. J. Environ. Res. Public Health 2012, 9 1941 factor kappa-B (NFκB) [13], mitogen-activated protein kinase (MAPK) [14], and Wnt/β-catenin pathways [15]. The aryl hydrocarbon receptor (AhR) pathway is also implicated in leukemogenesis [16], where, for example, primary human T-cell leukemia cells have shown up-regulated AhR expression and activation [17]. Furthermore, dysregulated AhR signaling within hematopoietic stem cells has been proposed as a possible mechanism linking benzene exposure to AML development [18]. 1.4. Previous Studies on miRNAs in AML Since the initial miRNA tumor classification studies [1], many other researchers have investigated miRNAs and their involvement in AML. For example, numerous studies have correlated miRNA expression levels to cytogenetics in AML patients with the goal of identifying diagnostic and prognostic indicators, as reviewed by Marcucci et al. [3]. Some studies have also correlated the expression levels of individual miRNAs with genome-wide mRNA expression levels, and identified subsets of genes likely regulated by individual miRNAs in AML. In cytogenetically normal AML patients, for example, miR-181a expression levels have been shown to inversely correlate with the expression of genes involved in innate immunity [19]. 1.5. Study Aim We hypothesize that miRNAs likely act in a concert to exert their biological functions. More specifically, we propose that the coordinated action of miRNAs on their transcriptional targets may influence key biological pathways involved in leukemogenesis. A recent paper [20] in which the role of multiple miRNAs on transcriptional regulation has been shown supports this hypothesis. What remains to be identified is whether a key biological pathway may be the target of such concerted miRNA control. Our study addresses this issue using a novel analytical strategy to compare epigenetically-regulated signaling within AML cells versus non-leukemia cells. While previous studies have identified associations between individual miRNAs and leukemia-related gene expression profiles, we employed a systems-level approach to identify converging pathways regulated by several key AML-associated miRNAs. We predicted that the statistical integration of existing databases, along with systems-level pathway analyses, would reveal high ranking biological pathways altered at both the gene expression and epigenetic (e.g., miRNA) level in AML patients. Thus, this study’s goal was to elucidate novel biological relationships that may underlie leukemogenesis. 2. Methods 2.1. Identifying the AML-Associated Gene Expression Signature In order to identify a genomic signature associated with AML, we performed a statistical analysis comparing gene expression levels between AML patients and non-leukemic individuals. Specifically, a publically available database containing microarray data from patients with AML (n = 202), myelodysplastic syndrome (n = 164), or from non-leukemic, control patients (n = 69) was downloaded from the National Center for Biotechnology Information’s Gene Expression Omnibus [21]. This dataset was generated in an investigation by Mills et al., where microarray-based classifiers were identified to predict the risk of AML transformation in patients with myelodysplastic syndrome [22].