A NOTCH 1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia

被引：352

作者：

Herranz, Daniel ^{[1
]}

Ambesi-Impiombato, Alberto ^{[1
]}

Palomero, Teresa ^{[1
,2
]}

Schnell, Stephanie A. ^{[1
]}

Belver, Laura ^{[1
]}

Wendorff, Agnieszka A. ^{[1
]}

Xu, Luyao ^{[1
]}

Castillo-Martin, Mireia ^{[3
]}

Llobet-Navas, David ^{[3
]}

Cordon-Cardo, Carlos ^{[3
]}

Clappier, Emmanuelle ^{[4
,5
]}

Soulier, Jean ^{[4
,5
]}

Ferrando, Adolfo A. ^{[1
,2
,6
]}

机构：

[1] Columbia Univ, Inst Canc Genet, New York, NY 10027 USA

[2] Columbia Univ, Dept Pathol, Med Ctr, New York, NY USA

[3] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA

[4] Hop St Louis, INSERM, UMR 944, Inst Univ Hematol, Paris, France

[5] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France

[6] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10027 USA

来源：

NATURE MEDICINE | 2014年 / 20卷 / 10期

基金：

欧洲研究理事会; 美国国家卫生研究院;

关键词：

C-MYC; APC DEFICIENCY; CANCER; EXPRESSION; MUTATIONS; VARIANT; MICE; SUSCEPTIBILITY; ACTIVATION; MECHANISMS;

D O I：

10.1038/nm.3665

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 NOTCH/-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.

引用

页码：1130 / 1137

页数：8

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