title: A set of miRNAs that involve in the pathways of drug resistance and leukemic stem-cell differentiation is associated with the risk of relapse and glucocorticoid response in childhood ALL.
abstract: 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.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Bo-Wei
authors.initials: BW
authors.lastname: Han
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Feng
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Li
authors.forename: Xue-Qun
authors.initials: XQ
authors.lastname: Luo
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Li
authors.forename: Xing-Ju
authors.initials: XJ
authors.lastname: Zhang
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Zheng
authors.forename: Cheng-Wu
authors.initials: CW
authors.lastname: Zeng
authors.forename: Kang-Yu
authors.initials: KY
authors.lastname: Lin
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.forename: Yue-Qin
authors.initials: YQ
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D016016:Proportional Hazards Models; D012008:Recurrence; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; C568528:MIRN708 microRNA, human; D035683:MicroRNAs