Epigenetic mechanisms result in changes to gene expression, without affecting the underlying DNA sequence. These mechanisms have been implicated in the onset of many diseases. The epigenetic mechanisms of DNA methylation and microRNA expression were interrogated to determine their role in paediatric acute myeloid leukaemia (AML). AML is highly heterogeneous, and approximately 20% of Australian children will die of this disease. Through genome-scale profiling we identified a number of differentially methylated regions present in paediatric AML compared to healthy controls. Here we focus on, and elucidate, the epigenetics of the DLEU2 non-coding RNA, as well as the embedded tumour suppressor microRNA cluster miR-15a/16-1 in paediatric AML. We identify a sub-category of patients with chromosome 11 abnormalities, or sole trisomy 8, which show a differential DNA methylation pattern which associates with miR-15a/16-1 expression, and additionally confers a better disease prognosis. We also show through the combination of methylation and microRNA interrogation the delineation of AML subtypes complementary to current clinical classification methods.