TEL-AML1 regulation of survivin and apoptosis via miRNA-494 and miRNA-320a.
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.
Diakos
Christofer
C
Laboratory for Molecular Epidemiology, University of California, San Francisco, San Francisco, CA, USA.
Zhong
Sheng
S
Xiao
Yuanyuan
Y
Zhou
Mi
M
Vasconcelos
Gisele M
GM
Krapf
Gerd
G
Yeh
Ru-Fang
RF
Zheng
Shichun
S
Kang
Michelle
M
Wiencke
John K
JK
Pombo-de-Oliveira
Maria S
MS
Panzer-Grümayer
Renate
R
Wiemels
Joseph L
JL
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
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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