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

Abstract:

: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 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.

journal_name

Blood

journal_title

Blood

authors

Wong RWJ,Ngoc PCT,Leong WZ,Yam AWY,Zhang T,Asamitsu K,Iida S,Okamoto T,Ueda R,Gray NS,Ishida T,Sanda T

doi

10.1182/blood-2017-06-792184

subject

Has Abstract

pub_date

2017-11-23 00:00:00

pages

2326-2338

issue

21

eissn

0006-4971

issn

1528-0020

pii

blood-2017-06-792184

journal_volume

130

pub_type

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