An Oncogenic Super-Enhancer Formed Through Somatic Mutation of a Noncoding Intergenic Element

By M. Mansour, B. Abraham, L. Anders, A. Berezovskaya, A. Gutierrez, A. Durbin, J. Etchin, Lee N. Lawton, S. Sallan, L. Silverman and 5 more. Science, 2014

678 citations recorded by the source corpus.

In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, that recruit much of the cell’s transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine 27 (H3K27ac). In a subset of T-cell acute lymphoblastic leukemia (T-ALL) cases, we found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB transcription factor in a precise noncoding site, which creates a super-enhancer upstream of the TAL1 oncogene. MYB binds to this new site and recruits its H3K27 acetylase–binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1, GATA-3, and TAL1 itself. Additionally, most endogenous super-enhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in super-enhancer initiation. Thus, this study identifies a genetic mechanism responsible for the generation of oncogenic super-enhancers in malignant cells. Leukemia-associated mutations drive cell growth by creating a powerful transcriptional enhancer upstream of an oncogene. [Also see Perspective by Vähärautio and Taipale] A super-enhancer in leukemia development Human cancer genome projects have provided a wealth of information about mutations that reside within the coding regions of genes and drive tumor growth by functionally altering protein products. However, this mutational portrait of cancer is incomplete: A growing number of mutations are being found within gene regulatory regions. Mansour et al. present an intriguing example of this in a study of a childhood cancer, T-cell acute lymphoblastic leukemia (see the Perspective by Vähärautio and Taipale). An oncogene known to drive the growth of this cancer is expressed at high levels in the leukemic cells because the cells harbor mutations that create a powerful superenhancer (a DNA sequence that activates transcription) upstream of the oncogene. Science, this issue p. 1373; see also p. 1291

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5e8d9eb2c79021c2bdad2a0bde749539c07862d7

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

Citations in the corpus

dbSUPER: a database of super-enhancers in mouse and human genome (2015, background): “extended the functional importance of super-enhancers by showing that somatic mutations introduce binding sites for the MYB transcription factor, which creates a powerful super-enhancer that mediates the overexpression of oncogenes in T-cell acute lymphoblastic leukaemia (T-ALL) (31,32).”
Transcriptional Addiction in Cancer (2017, neutral): “…DNA translocation (Affer et al., 2014; Drier et al., 2016; Groschel et al., 2014; Northcott et al., 2014; Walker et al., 2014), focal amplification (Hnisz et al., 2013; Shi et al., 2013; Zhang et al., 2016), and nucleation by small INDELs that create master TF binding sites (Mansour et al., 2014).”
THE GENOMIC LANDSCAPE OF PEDIATRIC AND YOUNG ADULT T-LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA (2017, positive): “We verified a subset of previously unreported or complex sequence mutations and mutations of the TAL1 enhancer 48,49 by amplicon-based next-generation sequencing ( Supplementary Table 6 ).”
Coactivator condensation at super-enhancers links phase separation and gene control (2018, background): “This high-density assembly at SEs has been shown to exhibit sharp transitions of formation and dissolution, forming as the consequence of a single nucleation event (19, 20) and collapsing when concentrated factors are depleted from chromatin (21–25) or when nucleation sites are deleted (26–29).”