Int. J. Environ. Res. Public Health 2012, 9 1945 levels in AML samples versus non-leukemic samples [29–34] (Table 1). Furthermore, all of these miRNAs are suggested to play roles in leukemogenesis [32,33,39–44]. miRNA miR-125b miR-126 miR-142-3p miR-155 miR-223 miR-29a miR-29b Table 1. AML-associated miRNA database. Reference(s) for Differential Expression in AML Patients [29] [30,31] [34] [31,33] [30] [30,32,34] [31] Reference(s) for Suggested Role in Leukemogenesis [39] [40] [41] [33] [42,44] [32] [43] 3.1.3. miRNA-Regulated Genes Are Predicted To understand genomic changes that occur in AML patients likely via changes in miRNA expression, we computationally predicted transcriptional targets of the seven AML-associated miRNAs. Using seed match-based algorithms, 196 genes were predicted to be targeted by miR-125b, 22 by miR-126, 308 by miR-142-3p, 164 by miR-155, 68 by miR-223, 805 by miR-29a, and 179 by miR-29b. In total, 1,589 unique genes were predicted to be targeted by at least one of the seven AML-associated miRNAs (see electronic supplementary information, Table S3). 3.1.4. The miRNA-Mediated AML Gene Signature Is Identified With the goal of identifying genes with altered expression levels in AML that are likely regulated by miRNAs, we compared the 731 genes of the AML-associated gene expression signature (identified in step 1 of the analysis) to the 1,589 genes predicted to be targeted by AML-associated miRNAs (identified in step 3 of the analysis). This comparison showed that 78 genes contained in the AML-associated gene signature are likely regulated by AML-associated miRNAs (see electronic supplementary information, Table S4). 3.1.5. The AML Signalisome Is Identified In order to identify whether the miRNA-mediated genomic changes occur in the context of high level interactions, molecular networks were constructed using the 78 AML-associated genes that were predicted to be regulated by the AML-associated miRNAs. A total of five significant (p value < 0.01) sub-networks were constructed (see electronic supplementary information, Table S5). Interestingly, four of the five sub-networks interact, which when combined, form the AML Signalisome (Figure 3). This AML Signalisome consists of 133 proteins, 53 of which are encoded by genes altered in AML and predicted to be targeted by AML-associated miRNAs.