Dysregulated microRNA (miRNA) expression contributes to the pathogenesis of 
hematopoietic malignancies, including chronic lymphocytic leukemia (CLL). 
However, an understanding of the mechanisms that cause aberrant miRNA 
transcriptional control is lacking. In this study, we comprehensively 
investigated the role and extent of miRNA epigenetic regulation in CLL. 
Genome-wide profiling conducted on 24 CLL and 10 healthy B cell samples revealed 
global DNA methylation patterns upstream of miRNA sequences that distinguished 
malignant from healthy cells and identified putative miRNA promoters. 
Integration of DNA methylation and miRNA promoter data led to the identification 
of 128 recurrent miRNA targets for aberrant promoter DNA methylation. DNA 
hypomethylation accounted for more than 60% of all aberrant promoter-associated 
DNA methylation in CLL, and promoter DNA hypomethylation was restricted to 
well-defined regions. Individual hyper- and hypomethylated promoters allowed 
discrimination of CLL samples from healthy controls. Promoter DNA methylation 
patterns were confirmed in an independent patient cohort, with 11 miRNAs 
consistently showing an inverse correlation between DNA methylation status and 
expression level. Together, our findings characterize the role of epigenetic 
changes in the regulation of miRNA transcription and create a repository of 
disease-specific promoter regions that may provide additional insights into the 
pathogenesis of CLL.