title: Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL.
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.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.forename: Takaomi
authors.initials: T
authors.lastname: Sanda
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.forename: Carl D
authors.initials: CD
authors.lastname: Novina
authors.forename: Harald
authors.initials: H
authors.lastname: von Boehmer
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D016259:Genes, myc; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008969:Molecular Sequence Data; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D051881:Receptor, Notch1 / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D051057:Proto-Oncogene Proteins c-akt; D051881:Receptor, Notch1; C531201:MIRN451 microRNA, human; C550758:Mirn451 microRNA, mouse; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; C075668:Tcf3 protein, mouse