title: 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.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Herranz
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ambesi-Impiombato
authors.affiliation: 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.
authors.forename: Teresa
authors.initials: T
authors.lastname: Palomero
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schnell
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Belver
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Wendorff
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Luyao
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo-Martin
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Llobet-Navás
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.affiliation: 1] INSERM, UMR 944, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France. [2] Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Clappier
authors.affiliation: 1] INSERM, UMR 944, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France. [2] Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.affiliation: 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.
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005260:Female; D005784:Gene Amplification; D016259:Genes, myc; D006801:Humans; D019169:Jurkat Cells; D038041:Lymphopoiesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D051881:Receptor, Notch1 / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism
chemical_list: C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1