Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia

Regina Wan Ju Wong, Phuong Cao Thi Ngoc, Wei Zhong Leong, Alice Wei Yee Yam, Tinghu Zhang, Kaori Asamitsu, Shinsuke Iida, Takashi Okamoto, Ryuzo Ueda, Nathanael S. Gray, Takashi Ishida and Takaomi Sanda

Key points

  • Enhancer profiling combined with gene expression analysis identifies CCR4 and TIAM2 as critical cancer genes in ATL.

  • Super-enhancers are enriched at genes involved in T-cell activation pathway in ATL, reflecting the origin of leukemia cells.


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. Identification of such enhancers would pinpoint critical factors that directly contribute to pathogenesis. Here, 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 IL2RA/CD25, CD30 and FYN, 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 CCR4, PIK3R1 and TP73, 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, TIAM2 that was associated with super-enhancers in all ATL samples but not in normal T-cells. Knockdown of TIAM2 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.

  • Submitted June 21, 2017.
  • Accepted September 22, 2017.