Noncoding Mutations Can Create Super-Enhancers

Monoallelic expression of the TAL1 oncogene arises in 25% of T-cell acute lymphoblastic leukemias (T-ALL) from an 80-kilobase deletion that fuses activating regulatory elements to the TAL1 coding sequence. However, in a subset of T-ALLs, monoallelic TAL1 expression is not associated with this chromosomal deletion. Mansour and colleagues found that several T-ALL cell lines and 8 of 146 (5.5%) pediatric T-ALL samples harbored somatic heterozygous insertions ranging from 2 to 18 base pairs at a specific site that overlapped with a region of extensive histone H3 lysine 27 acetylation (H3K27ac) upstream of the TAL1 transcription start site. The widespread H3K27ac at this locus was consistent with features of super-enhancers and not present in normal thymocytes or hematopoietic stem and progenitor cells or in T-ALL cells lacking the insertions. Every insertion introduced one or more binding motifs for the transcription factor MYB in a genomic region where there were normally none, and MYB was required for the activity of the enhancer in vitro and for expression of TAL1 in insertion-positive T-ALL cell lines. The insertion of MYB binding sites was also associated with broad recruitment of the H3K27 acetyltransferase CBP, RNA polymerase II, Mediator, and members of a leukemic transcriptional factor complex, further suggesting that the insertions serve to create an aberrant de novo super-enhancer that drives monoallelic TAL1 expression. Consistent with this possibility, disruption of the insertion, but not the wild-type sequence, in T-ALL cells using CRISPR/Cas9 technology completely abrogated TAL1 expression and led to collapse of the TAL1 super-enhancer, as demonstrated by total loss of MYB binding and H3K27ac. These findings thus establish that somatic noncoding DNA mutations can drive oncogene expression by inducing de novo transcription factor binding to initiate the aberrant creation of super-enhancers.

Mansour MR, Abraham BJ, Anders L, Berezovskaya A, Gutierrez A, Durbin AD, et al. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 2014;346:1373–7.

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