Wong Regina Wan Ju, Ngoc Phuong Cao Thi, Leong Wei Zhong, Yam Alice Wei Yee, Zhang Tinghu, Asamitsu Kaori, Iida Shinsuke, Okamoto Takashi, Ueda Ryuzo, Gray Nathanael S, Ishida Takashi, Sanda Takaomi
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
Blood. 2017 Nov 23;130(21):2326-2338. doi: 10.1182/blood-2017-06-792184. Epub 2017 Oct 4.
A number of studies have recently demonstrated that super-enhancers, which are large cluster of enhancers typically marked by a high level of acetylation of histone H3 lysine 27 and mediator bindings, are frequently associated with genes that control and define cell identity during normal development. Super-enhancers are also often enriched at cancer genes in various malignancies. The identification of such enhancers would pinpoint critical factors that directly contribute to pathogenesis. In this study, we performed enhancer profiling using primary leukemia samples from adult T-cell leukemia/lymphoma (ATL), which is a genetically heterogeneous intractable cancer. Super-enhancers were enriched at genes involved in the T-cell activation pathway, including , and in both ATL and normal mature T cells, which reflected the origin of the leukemic cells. Super-enhancers were found at several known cancer gene loci, including , and , in multiple ATL samples, but not in normal mature T cells, which implicated those genes in ATL pathogenesis. A small-molecule CDK7 inhibitor, THZ1, efficiently inhibited cell growth, induced apoptosis, and downregulated the expression of super-enhancer-associated genes in ATL cells. Furthermore, enhancer profiling combined with gene expression analysis identified a previously uncharacterized gene, , that was associated with super-enhancers in all ATL samples, but not in normal T cells. Knockdown of induced apoptosis in ATL cell lines, whereas overexpression of this gene promoted cell growth. Our study provides a novel strategy for identifying critical cancer genes.
最近的一些研究表明,超级增强子是一大簇增强子,通常以组蛋白H3赖氨酸27的高水平乙酰化和中介体结合为特征,在正常发育过程中经常与控制和定义细胞身份的基因相关联。超级增强子在各种恶性肿瘤的癌症基因中也常常富集。鉴定此类增强子将找出直接导致发病机制的关键因素。在本研究中,我们使用来自成人T细胞白血病/淋巴瘤(ATL)的原发性白血病样本进行增强子分析,ATL是一种具有遗传异质性的难治性癌症。在ATL和正常成熟T细胞中,超级增强子在参与T细胞激活途径的基因(包括 、 和 )上富集,这反映了白血病细胞的起源。在多个ATL样本中,在几个已知的癌症基因位点(包括 、 和 )发现了超级增强子,但在正常成熟T细胞中未发现,这表明这些基因与ATL发病机制有关。一种小分子CDK7抑制剂THZ1能有效抑制ATL细胞的生长、诱导凋亡并下调超级增强子相关基因的表达。此外,增强子分析与基因表达分析相结合,鉴定出一个以前未被表征的基因 ,该基因在所有ATL样本中与超级增强子相关,但在正常T细胞中不相关。敲低 在ATL细胞系中诱导凋亡,而该基因的过表达促进细胞生长。我们的研究为鉴定关键癌症基因提供了一种新策略。