title: Classification of pediatric acute myeloid leukemia based on miRNA expression profiles.
abstract: 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.
authors.affiliation: Pediatric Oncology-Hematology, Erasmus MC, Sophia Children's Hospital, The Netherlands.
authors.forename: Askar
authors.initials: A
authors.lastname: Obulkasim
authors.affiliation: Pediatric Oncology-Hematology, Erasmus MC, Sophia Children's Hospital, The Netherlands.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Katsman-Kuipers
authors.affiliation: Pediatric Oncology-Hematology, Erasmus MC, Sophia Children's Hospital, The Netherlands.
authors.forename: Lonneke
authors.initials: L
authors.lastname: Verboon
authors.affiliation: Department of Hematology, ErasmusMC, Rotterdam, The Netherlands.
authors.forename: Mathijs
authors.initials: M
authors.lastname: Sanders
authors.affiliation: Department of Hematology, ErasmusMC, Rotterdam, The Netherlands.
authors.forename: Ivo
authors.initials: I
authors.lastname: Touw
authors.affiliation: Department of Hematology, ErasmusMC, Rotterdam, The Netherlands.
authors.forename: Mojca
authors.initials: M
authors.lastname: Jongen-Lavrencic
authors.affiliation: Pediatric Oncology-Hematology, Erasmus MC, Sophia Children's Hospital, The Netherlands.|Prinses Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, German.
authors.forename: Jan-Henning
authors.initials: JH
authors.lastname: Klusmann
authors.affiliation: Pediatric Oncology-Hematology, Erasmus MC, Sophia Children's Hospital, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Michel Zwaan
authors.affiliation: Pediatric Oncology-Hematology, Erasmus MC, Sophia Children's Hospital, The Netherlands.|Prinses Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.affiliation: Pediatric Oncology-Hematology, Erasmus MC, Sophia Children's Hospital, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Fornerod
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002648:Child; D007446:Chromosome Inversion; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000145:classification* / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D014178:Translocation, Genetic
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D035683:MicroRNAs; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin
keywords: acute myeloid leukemia; classification; cytogenetic aberration; microRNA; pediatric