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Nat Med. 2014 Oct;20(10):1130-7. doi: 10.1038/nm.3665. Epub 2014 Sep 7.

A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia.

Author information

1
Institute for Cancer Genetics, Columbia University, New York, New York, USA.
2
1] Institute for Cancer Genetics, Columbia University, New York, New York, USA. [2] Department of Pathology, Columbia University Medical Center, New York, New York, USA.
3
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
4
1] INSERM, UMR 944, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France. [2] Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
5
1] Institute for Cancer Genetics, Columbia University, New York, New York, USA. [2] Department of Pathology, Columbia University Medical Center, New York, New York, USA. [3] Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.

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.

PMID:
25194570
PMCID:
PMC4192073
DOI:
10.1038/nm.3665
[Indexed for MEDLINE]
Free PMC Article

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