title: Glucocorticoid-regulated microRNAs and mirtrons in acute lymphoblastic leukemia.
abstract: Glucocorticoids (GCs) induce apoptosis in lymphoid lineage cells and are therefore used in the therapy of acute lymphoblastic leukemia (ALL) and related malignancies. MicroRNAs (miRNAs) and the related mirtrons are ~22 nucleotide RNAs derived from polymerase-II transcripts and implicated in the control of essential biological functions, including apoptosis. Whether GCs regulate miRNA-encoding transcription units is unknown. We investigated miRNA/mirtron expression and GC regulation in 8 leukemia/lymphoma in vitro models and 13 ALL children undergoing systemic GC monotherapy using a combination of expression profiling techniques, real time reverse transcription (RT)-PCR and northern blotting to detect mature miRNAs and/or their precursors. We found that mature miRNA regulations can be inferred from expression data of their host genes. Although a simple miRNA-initiated canonical pathway to GC-induced apoptosis or cell cycle arrest did not emerge, we identified several miRNAs/mirtrons that were regulated by GC in patients and cell lines, including the myeloid-specific miR-223 and the apoptosis and cell cycle arrest-inducing miR15 ~ 16 clusters. In an in vitro model, overexpression of miR15b ~ 16 mimics increased and silencing by miR15b ~ 16 inhibitors decreased GC sensitivity. Thus, the observed complex changes in miRNA/mirtron expression during GC treatment might contribute to the anti-leukemic GC effects in a cell context-dependent manner.
authors.affiliation: Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Rainer
authors.forename: C
authors.initials: C
authors.lastname: Ploner
authors.forename: S
authors.initials: S
authors.lastname: Jesacher
authors.forename: A
authors.initials: A
authors.lastname: Ploner
authors.forename: M
authors.initials: M
authors.lastname: Eduardoff
authors.forename: M
authors.initials: M
authors.lastname: Mansha
authors.forename: M
authors.initials: M
authors.lastname: Wasim
authors.forename: R
authors.initials: R
authors.lastname: Panzer-Grümayer
authors.forename: Z
authors.initials: Z
authors.lastname: Trajanoski
authors.forename: H
authors.initials: H
authors.lastname: Niederegger
authors.forename: R
authors.initials: R
authors.lastname: Kofler
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D004257:DNA Polymerase II / Q000235:genetics; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D035683:MicroRNAs / Q000032:analysis* / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012333:RNA, Messenger
chemical_list: D004257:DNA Polymerase II; D005938:Glucocorticoids; D035683:MicroRNAs; D012333:RNA, Messenger; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; C525067:MIR223, human