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

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.

Nature Medicine 20, 1130–1137 (2014) doi:10.1038/nm.3665 | Received 25 May 2014 | Accepted 23 July 2014 | Published online 07 September 2014

Daniel Herranz, Alberto Ambesi-Impiombato, Teresa Palomero, Stephanie A Schnell, Laura Belver, Agnieszka A Wendorff, Luyao Xu, Mireia Castillo-Martin, David Llobet-Navás, Carlos Cordon-Cardo, Emmanuelle Clappier, Jean Soulier & Adolfo A Ferrando