Relapse is a major challenge in the successful treatment of childhood
acute lymphoblastic leukemia (ALL). Despite intensive research efforts, the mechanisms of ALL relapse are still not fully understood. An understanding of the molecular mechanisms underlying treatment outcome,
therapy response and the biology of relapse is required. In this study, we carried out a genome-wide
microRNA (
miRNA) microarray analysis to determine the
miRNA expression profiles and relapse-associated
miRNA patterns in a panel of matched diagnosis-relapse or diagnosis-complete remission (CR)
childhood ALL samples. A set of
miRNAs differentially expressed either in relapsed patients or at diagnosis compared with CR was further validated by quantitative real-time polymerase chain reaction in an independent sample set. Analysis of the predicted functions of target genes based on gene ontology 'biological process' categories revealed that the abnormally expressed
miRNAs are associated with
oncogenesis, classical multidrug resistance pathways and leukemic stem cell self-renewal and differentiation pathways. Several targets of the
miRNAs associated with ALL relapse were experimentally validated, including FOXO3, BMI1 and E2F1. We further investigated the association of these dysregulated
miRNAs with clinical outcome and confirmed significant associations for miR-708, miR-223 and miR-27a with individual relapse-free survival. Notably, miR-708 was also found to be associated with the in vivo
glucocorticoid therapy response and with disease risk stratification. These
miRNAs and their targets might be used to optimize anti-leukemic
therapy, and serve as novel targets for development of new countermeasures of
leukemia. This fundamental study may also contribute to establish the mechanisms of relapse in other
cancers.