Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.
Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.
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DOI：
10.1126/science.1259037
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发表时间：
2014-12-12
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作者：
Mansour MR;Abraham BJ;Anders L;Berezovskaya A;Gutierrez A;Durbin AD;Etchin J;Lawton L;Sallan SE;Silverman LB;Loh ML;Hunger SP;Sanda T;Young RA;Look AT
在某些人类癌症中，关键癌基因的表达是由称为超级增强子的大型调控元件驱动的，超级增强子招募细胞的大部分转录装置，并由组蛋白H3赖氨酸27（H3 K27 ac）的广泛乙酰化定义。在T细胞急性淋巴细胞白血病（T-ALL）病例的一个子集中，我们发现获得杂合子体细胞突变，在精确的非编码位点引入MYB转录因子的结合基序，这在TAL 1癌基因上游产生了一个超级增强子。MYB与这个新位点结合，并招募它的H3 K27乙酰化酶结合伴侣CBP，以及包含RUNX 1，加塔-3和TAL 1本身的主要致白血病转录复合物的核心组分。此外，在T-ALL细胞中发现的大多数内源性超级增强子被MYB和CBP占据，表明MYB在超级增强子起始中的一般作用。因此，这项研究确定了一种遗传机制，负责在恶性细胞中产生致癌的超级增强子。
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.