biostudies-literatureLi XNIAID NIH HHSNCI NIH HHS663-75https://www.ebi.ac.uk/biostudies/studies/S-EPMC3135352biostudies-literatureUnknown208(4)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 iThe Journal of experimental medicineRepression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL.PMC3135352P30 AI0603545P01CA109901P01 CA0684845P01CA68484P01 CA109901Li XLook ATvon Boehmer HSanda TNovina CDfalseRepression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL.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 i2011-01-01T00:00:00Z2011 Apr2025-04-22T20:37:50.68Z2019-03-27T03:07:01ZS-EPMC31353522146422210.1084/jem.20102384