An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element

Abstract

In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, which 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 it’s 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, suggesting 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.

Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia

“…Recently, a subset of T-ALL patients was found to harbor mutations near the oncogenic TAL1 locus that leads to establishment of a highly active SE via MYB binding (Mansour et al 2014). We observed enrichment of E/R-regulated RUNX1 binding sites in SEs.…”

“…They consist of enhancers with clustering of binding sites for multiple TFs and high histone K27 acetylation levels, reminiscent of locus control regions characterized at beta-globin or immune gene loci (Li et al 2002;Whyte et al 2013;Pott and Lieb 2014;Adam et al 2015). Recently, aberrant enhancer activity at the TAL1 gene locus was shown to drive leukemogenesis in T-ALL (Mansour et al 2014). However, the majority of cancer-relevant regulatory elements remain uncharacterized.…”

Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma

“…14 A recent study has shown that an oncogenic super-enhancer forms through somatic mutation in a noncoding intergenic region and contributes to tumorigenesis in a subset of T cell acute lymphoblastic leukemia. 24 Additionally, enhancer activity has been linked to resistance to Notch inhibitor in T-cell leukemia. 25 Finally, emerging data suggests enhancer RNAs play a role in regulation of gene expression.…”

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

“…[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] Most ALL genomes harbor sequence and structural DNA alterations involving coding genes, as well as alterations of noncoding elements such as noncoding RNAs 23 and enhancer elements. 24,25 Here, we consider results from these studies in several categories: (1) identification of new subtypes of ALL that lack recurring gross chromosomal alterations; (2) characterization of the constellations of genetic alterations that define each ALL subtype; (3) the relationship between genetic alterations, clonal heterogeneity, and relapse; (4) identification of inherited genetic variants and mutations linked to ALL susceptibility and outcome; (5) and translating new discoveries to improved diagnostic, prognostic, and precision medicine approaches.…”

“…76 Another mechanism of leukemogenesis in T-ALL is mutations upstream of the T-ALL oncogene TAL1, which generate a binding site for the MYB transcription factor, thereby recruiting a protein complex including TAL1 and the H3K27 acetylator CREBBP, resulting in formation of an oncogenic "superenhancer" region characterized by high levels of H3K27 acetylation. 25 These examples underscore the importance of careful integrated analysis of coding and noncoding genomic, transcriptomic, and epigenomic features in ALL.…”