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

作者：Mansour, Marc R.; Abraham, Brian J.; Anders, Lars; Berezovskaya, Alla; Gutierrez, Alejandro; Durbin, Adam D.; Etchin, Julia; Lawton, Lee; Sallan, Stephen E.; Silverman, Lewis B.; Loh, Mignon L.; Hunger, Stephen P.; Sanda, Takaomi; Young, Richard A.; Look, A. Thomas^*

来源：Science, 2014, 346(6215): 1373-1377.

DOI：10.1126/science.1259037

• ACUTE LYMPHOBLASTIC-LEUKEMIA
• MONOALLELIC EXPRESSION
• TRANSCRIPTION FACTORS
• SELECTIVE-INHIBITION
• CELL IDENTITY
• TAL1 COMPLEX
• GENES
• DISRUPTION
• DISEASE
• LINEAGE

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.

• 出版日期2014-12-12