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

ABSTRACT: In many cancers, critical oncogenes are driven from large regulatory elements, called super-enhancers, which recruit much of the cell’s transcriptional apparatus and are defined by extensive H3K27 acetylation. We found that in T-cell acute lymphoblastic leukemia (T-ALL), somatic heterozygous mutations introduce MYB binding motifs in a precise noncoding site, which nucleate a super-enhancer upstream of the TAL1 oncogene. Further analysis of genome-wide binding identified MYB and its histone acetylase binding partner CBP as core components of the TAL1 complex and of the TAL1-mediated feed-forward auto-regulatory loop that drives T-ALL. Furthermore, MYB and CBP occupy endogenous MYB binding sites in the majority of super-enhancer sites found in T-ALL cells. Thus, our study reveals a new mechanism for the generation of super-enhancers in malignant cells involving the introduction of somatic indel mutations within non-coding sequences, which introduce aberrant binding sites for the MYB master transcription factor. ChIP-Seq for transcription factors and co-factors in T cell acute lymphoblastic leukemia cell lines

ORGANISM(S): Homo sapiens  

SUBMITTER: Stephen E Sallan  Alla Berezovskaya   Lewis B Silverman   Alejandro Gutierrez   Takaomi Sanda   Mignon L Loh   Stephen P Hunger   Richard A Young   Lars Anders   Jessica Reddy   Brian J Abraham   Lee N Lawton   A T Look   Adam D Durbin   Marc R Mansour    

PROVIDER: E-GEOD-59657 | ArrayExpress | 2014-11-28



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