Regulatory Networks Governed by MicroRNAs in T-ALL Oncogenesis and Normal T-Cell Development

Abstract 1366

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes affecting children, adolescents and adults. T-ALL is characterized by a differentiation arrest at specific stages of T-cell development, primarily originating from the ectopic expression of T-cell oncogenes. Based on the mutation status of these genes and mRNA profiles, at least 5 different molecular-cytogenetic subgroups have been delineated. In addition, genetic abnormalities affecting cell cycle, proliferation, survival and self-renewal are present in all T-ALL subgroups. In a recent study, we discovered five oncogenic microRNAs (miRNAs) co-regulating the expression of key tumor suppressor genes implicated in the pathogenesis of T-ALL (Mavrakis et al., Nature Genetics, 2011). In this study, we established the extended miRNAome (756 miRNAs) in a genetically well characterized T-ALL patient cohort (n=65), 20 T-ALL cell lines as well as 9 different subsets of sorted T-cell populations from 3 human donors in parallel to mRNA and gene copy number profiles thus allowing integrative data mining. Cross-comparison between the different datasets resulted in the identification of miRNAs with presumed function in normal T-cell development as well as novel candidate miRNAs in T-ALL pathogenesis. The candidates were validated in an independent patient series (n=50). To better understand our previously established miRNA-mRNA regulatory T-cell/T-ALL network, we performed miRNA-mRNA correlation analysis followed by gene set enrichment analysis in order to assign putative functions to the selected miRNAs (http://www.mirnabodymap.org/; Mestdagh et al., Nucleic Acids Research, in press). In addition, the regulatory network was consolidated and extended through identification of miRNAs targeting selected key T-ALL oncogenes and tumor suppressor genes using a robust high throughput 3'UTR screening assay. In conclusion, this study further details the regulatory networks controlling normal T-cell development and T-ALL oncogenesis.