Acute myeloid leukemia (AML) encompasses a large number of morphologically similar but at the molecular level quite distinct variants. Recurrent cytogenetic aberrations have been shown to constitute markers of diagnostic and prognostic value. However, despite recent successes in detecting novel molecular markers like FLT3, CEBPA, and NPM1 mutations, and despite recent advances in gene expression profiling treatment stratification is still difficult and the biology underlying distinct AML subclasses is still not fully understood. Recently, deregulated-expression of microRNAs (miRNAs) has been correlated with various cancers including leukemias, and evidence was provided that miRNAs can function both as oncogenes and tumor suppressors. In order to determine a potential role of differential miRNA expression in AML we profiled miRNA expression in a large series of adult AML patients to better characterize AML on the molecular level. Thus, we analyzed 91 samples which encompass the spectrum of cytogenetic and molecular genetic aberrations in AML using DNA microarray technology. We used a miRNA microarray platform validated by quantitative RT-PCR and Northern Blot analyses that contained approximately 250 human miRNAs. By unsupervised hierarchical cluster analysis of our 91 AML samples based on the miRNA expression of 202 filtered miRNAs we were able to identify two large AML subgroups. While these two groups were in part characterized by the differential expression of the miR-17-92 cluster, which recently has been identified to be deregulated in many cancer types, especially Myc-regulated tumors, we also identified several miRNAs not yet known to be differentially expressed in leukemia. Interestingly, correlation of the unsupervised cluster defined groups revealed an association with leukemia morphology as determined by FAB (French-American-British) classification, but there was no significant correlation with cytogenetically or molecular-genetically defined leukemia AML subgroups. On the other hand, by supervised analysis using the significance analysis of microarrays (SAM) methodology we were able to identify miRNA signatures characterizing acute promyelocytic leukemias with a t(15;17) and normal karyotype AML carrying mutations of NPM1. While these findings already support a potential role of differential miRNA expression in AML pathogenesis, future analyses correlating miRNA expression with global gene expression, which are currently underway, are likely to provide additional insights into AML biology, thereby helping to unravel the role of miRNAs in leukemogenesis.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA