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- Title
A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia.
- Authors
Herranz, Daniel; Ambesi-Impiombato, Alberto; Palomero, Teresa; Schnell, Stephanie A; Belver, Laura; Wendorff, Agnieszka A; Xu, Luyao; Castillo-Martin, Mireia; Llobet-Navás, David; Cordon-Cardo, Carlos; Clappier, Emmanuelle; Soulier, Jean; Ferrando, Adolfo A
- Abstract
Efforts to identify and annotate cancer driver genetic lesions have been focused primarily on the analysis of protein-coding genes; however, most genetic abnormalities found in human cancer are located in intergenic regions. Here we identify a new long range-acting MYC enhancer controlled by NOTCH1 that is targeted by recurrent chromosomal duplications in human T cell acute lymphoblastic leukemia (T-ALL). This highly conserved regulatory element, hereby named N-Me for NOTCH MYC enhancer, is located within a broad super-enhancer region +1.47 Mb from the MYC transcription initiating site, interacts with the MYC proximal promoter and induces orientation-independent MYC expression in reporter assays. Moreover, analysis of N-Me knockout mice demonstrates a selective and essential role of this regulatory element during thymocyte development and in NOTCH1-induced T-ALL. Together these results identify N-Me as a long-range oncogenic enhancer implicated directly in the pathogenesis of human leukemia and highlight the importance of the NOTCH1-MYC regulatory axis in T cell transformation and as a therapeutic target in T-ALL.
- Subjects
T cells; LYMPHOBLASTIC leukemia; MYC oncogenes; GENE enhancers; THYMOCYTES; NOTCH genes
- Publication
Nature Medicine, 2014, Vol 20, Issue 10, p1130
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.3665