TEL-AML1 regulation of survivin and apoptosis via miRNA-494 and miRNA-320a
Copyright policy )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.
- University of California, San Francisco United States
- Instituto Nacional do Câncer Brazil
Chromatin Immunoprecipitation, Adolescent, Oncogene Proteins, Fusion, Reverse Transcriptase Polymerase Chain Reaction, Survivin, Blotting, Western, Gene Expression, Apoptosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Inhibitor of Apoptosis Proteins, Gene Expression Regulation, Neoplastic, MicroRNAs, Cell Line, Tumor, Child, Preschool, Core Binding Factor Alpha 2 Subunit, Humans, RNA, Messenger, Child, Microtubule-Associated Proteins, Oligonucleotide Array Sequence Analysis
Chromatin Immunoprecipitation, Adolescent, Oncogene Proteins, Fusion, Reverse Transcriptase Polymerase Chain Reaction, Survivin, Blotting, Western, Gene Expression, Apoptosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Inhibitor of Apoptosis Proteins, Gene Expression Regulation, Neoplastic, MicroRNAs, Cell Line, Tumor, Child, Preschool, Core Binding Factor Alpha 2 Subunit, Humans, RNA, Messenger, Child, Microtubule-Associated Proteins, Oligonucleotide Array Sequence Analysis
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