Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL

被引:101
作者
Li, Xiaoyu [1 ]
Sanda, Takaomi [2 ]
Look, A. Thomas [2 ]
Novina, Carl D. [1 ]
von Boehmer, Harald [1 ]
机构
[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA
[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA
关键词
ACUTE LYMPHOBLASTIC-LEUKEMIA; C-MYC; LYMPHOCYTIC-LEUKEMIA; CELL DEVELOPMENT; GLIOMA-CELLS; NOTCH1; EXPRESSION; GENE; TARGETS; CANCER;
D O I
10.1084/jem.20102384
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:663 / 675
页数:13
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