Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL.
J Exp Med, 2011/4/11;208(4):663-75.
Li X[1], Sanda T, Look AT, Novina CD, von Boehmer H
Affiliations
PMID: 21464222DOI: 10.1084/jem.20102384
Impact factor: 17.579
Abstract
The NOTCH1 signaling pathway is a critical determinant of cell fate decisions and drives oncogenesis through mechanisms that are incompletely understood. Using an established mouse model of T cell acute lymphoblastic leukemia (T-ALL), here we report that induction of intracellular Notch1 (ICN1) leads to repression of miR-451 and miR-709. ICN1 decreases expression of these miRNAs by inducing degradation of the E2a tumor suppressor, which transcriptionally activates the genes encoding miR-451 and miR-709. Both miR-451 and miR-709 directly repress Myc expression. In addition, miR-709 directly represses expression of the Akt and Ras-GRF1 oncogenes. We also show that repression of miR-451 and miR-709 expression is required for initiation and maintenance of mouse T-ALL. miR-451 but not miR-709 is conserved in humans, and human T-ALLs with activating NOTCH1 mutations have decreased miR-451 and increased MYC levels compared with T-ALLs with wild-type NOTCH1. Thus, miR-451 and miR-709 function as potent suppressors of oncogenesis in NOTCH1-induced mouse T-ALL, and miR-451 influences MYC expression in human T-ALL bearing NOTCH1 mutations.
MeSH terms
Animals; Base Sequence; Basic Helix-Loop-Helix Transcription Factors; Genes, myc; Genes, ras; Humans; Mice; Mice, Inbred BALB C; MicroRNAs; Molecular Sequence Data; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-akt; Receptor, Notch1
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