title: TEL-AML1 regulation of survivin and apoptosis via miRNA-494 and miRNA-320a.
abstract: There is increasing evidence that miRNA and transcription factors interact in an instructive fashion in normal and malignant hematopoiesis. We explored the impact of TEL-AML1 (ETV6-RUNX1), the most common fusion protein in childhood leukemia, on miRNA expression and the leukemic phenotype. Using RNA interference, miRNA expression arrays, and quantitative polymerase chain reaction, we identified miRNA-494 and miRNA-320a to be up-regulated upon TEL-AML1 silencing independently of TEL expression. Chromatin immunoprecipitation analysis identified miRNA-494 as a direct miRNA target of the fusion protein TEL-AML1. Using bioinformatic analysis as well as functional luciferase experiments, we demonstrate that survivin is a target of the 2 miRNAs. miRNA-494 and miRNA-320a were introduced to the cells by transfection and survivin expression determined by Western blot analysis. These miRNAs blocked survivin expression and resulted in apoptosis in a similar manner as TEL-AML1 silencing by itself; this silencing was also shown to be Dicer-dependent. miRNAs-494 and -320a are expressed at lower levels in TEL-AML1+ leukemias compared with immunophenotype-matched nonTEL-AML1 acute lymphoblastic leukemia subtypes, and within TEL-AML1+ leukemias their expression is correlated to survivin levels. In summary our data suggest that TEL-AML1 might exert its antiapoptotic action at least in part by suppressing miRNA-494 and miRNA-320a, lowering their expression causing enhanced survivin expression.
authors.affiliation: Laboratory for Molecular Epidemiology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Christofer
authors.initials: C
authors.lastname: Diakos
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhong
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xiao
authors.forename: Mi
authors.initials: M
authors.lastname: Zhou
authors.forename: Gisele M
authors.initials: GM
authors.lastname: Vasconcelos
authors.forename: Gerd
authors.initials: G
authors.lastname: Krapf
authors.forename: Ru-Fang
authors.initials: RF
authors.lastname: Yeh
authors.forename: Shichun
authors.initials: S
authors.lastname: Zheng
authors.forename: Michelle
authors.initials: M
authors.lastname: Kang
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.forename: Maria S
authors.initials: MS
authors.lastname: Pombo-de-Oliveira
authors.forename: Renate
authors.initials: R
authors.lastname: Panzer-Grümayer
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
mesh_terms: D000293:Adolescent; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D047369:Chromatin Immunoprecipitation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D035683:MicroRNAs / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D014162:Transfection; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D051034:Inhibitor of Apoptosis Proteins; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D000077022:Survivin; C107489:BIRC5 protein, human; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein
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