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Pediatric acute myeloid leukemia (AML) is a heterogeneous disease with respect to biology as well as outcome. In this study, we investigated whether known biological subgroups of pediatric AML are reflected by a common microRNA (miRNA) expression pattern. We assayed 665 miRNAs on 165 pediatric AML samples. First, unsupervised clustering was performed to identify patient clusters with common miRNA expression profiles. Our analysis unraveled 14 clusters, seven of which had a known (cyto-)genetic denominator. Finally, a robust classifier was constructed to discriminate six molecular aberration groups: 11q23-rearrangements, t(8;21)(q22;q22), inv(16)(p13q22), t(15;17) (q21;q22), NPM1 and CEBPA mutations. The classifier achieved accuracies of 89%, 95%, 95%, 98%, 91% and 96%, respectively. Although lower sensitivities were obtained for the NPM1 and CEBPA (32% and 66%), relatively high sensitivities (84%-94%) were attained for the rest. Specificity was high in all groups (87%-100%). Due to a robust double-loop cross validation procedure employed, the classifier only employed 47 miRNAs to achieve the aforementioned accuracies. To validate the 47 miRNA signatures, we applied them to a publicly available adult AML dataset. Albeit partial overlap of the array platforms and molecular differences between pediatric and adult AML, the signatures performed reasonably well. This corroborates our claim that the identified miRNA signatures are not dominated by sample size bias in the pediatric AML dataset. In conclusion, cytogenetic subtypes of pediatric AML have distinct miRNA expression patterns. Reproducibility of the miRNA signatures in adult dataset suggests that the respective aberrations have a similar biology both in pediatric and adult AML.

The most important reason for therapy failure in pediatric acute myeloid leukemia (AML) is relapse. In order to identify miRNAs that contribute to the clonal evolution towards relapse in pediatric AML, miRNA expression profiling of 127 de novo pediatric AML cases were used. In the diagnostic phase, no miRNA signatures could be identified that were predictive for relapse occurrence, in a large pediatric cohort, nor in a nested mixed lineage leukemia (MLL)-rearranged pediatric cohort. AML with MLL- rearrangements are found in 15-20% of all pediatric AML samples, and reveal a relapse rate up to 50% for certain translocation partner subgroups. Therefore, microRNA expression profiling of six paired initial diagnosis-relapse MLL-rearranged pediatric AML samples (test cohort) and additional eight paired initial diagnosis-relapse samples with MLL-rearrangements (validation cohort) was performed. A list of 53 differentially expressed miRNAs was identified of which the miR-106b~25 cluster, located in intron 13 of MCM7, was the most prominent. These differentially expressed miRNAs however could not predict a relapse in de novo AML samples with MLL-rearrangements at diagnosis. Furthermore, higher mRNA expression of both MCM7 and its upstream regulator E2F1 was found in relapse samples with MLL-rearrangements. In conclusion, we identified the miR-106b~25 cluster to be upregulated in relapse pediatric AML with MLL-rearrangements., Competing Interests: The authors declare no conflicts of interest.

Background: miRNAs regulate gene expression, and thus play an important role in critical cellular processes. Aberrant miRNA expression patterns have been found in various types of cancer. So far, information about the expression of miRNAs in pediatric acute myeloid leukemia is limited., Procedure: We studied expression of miR-29a, -155, -196a, and -196b by stem-loop based RT-qPCR in 82 pediatric acute myeloid leukemia patients selected to represent relevant cytogenetic and molecular subgroups., Results: High miR-196a and -b expression was observed in patients carrying MLL gene rearrangements (P < 0.001), NPM1 mutations (P < 0.001), or FLT3-ITD in a cytogenetically normal background (P ≤ 0.02), compared to all other patients. In contrast, CEBPA mutated cases had a low expression of miR-196a and -b (P ≤ 0.001). Expression of miR-196a and -b was correlated with expression of neighboring HOXA and HOXB genes (Spearman's r = 0.46-0.82, P < 0.01). Expression of miR-155 was not related to cytogenetic features but high expression of miR-155 was observed in FLT3-ITD (P = 0.001) and NPM1-mutated cases (P = 0.04). Lower miR-29a expression was mainly observed in MLL-rearranged pediatric acute myeloid leukemia, specifically in cases carrying t(10;11) (P < 0.001)., Conclusions: We show aberrant expression of specific miRNAs in clinically relevant cytogenetic and molecular subgroups of pediatric acute myeloid leukemia, suggesting a role for these miRNAs in the underlying biology in these specific subgroups., (Copyright © 2011 Wiley Periodicals, Inc.)