SUPER-ENHANCER PROFILING IDENTIFIES CRITICAL CANCER GENES AND CHARACTERIZES CELL IDENTITY IN ADULT T-CELL LEUKEMIA

Abstract

Super-enhancers, a cluster of enhancers marked by a high level of acetylation of histone H3 lysine 27, are enriched at cancer genes in various malignancies. Identification of such enhancers would pinpoint critical factors that directly contribute to pathogenesis. Enhancer profiling using primary leukemia samples from adult T-cell leukemia/lymphoma (ATL) revealed that super-enhancers were enriched at genes involved in the T-cell activation pathway including IL2RA/CD25 in both ATL and normal mature T-cells, which reflected the origin of the leukemic cells. Super-enhancers at the CCR4 gene, a known ATL cancer gene, were observed in all ATL samples. A small-molecule CDK7 inhibitor efficiently downregulated the expression of these genes and inhibited cell growth. Additionally, we identified previously-uncharacterized genes, TIAM2 and BIRC3 that were associated with super-enhancers specifically in ATL samples but not in normal mature T-cells. Our study provides a novel strategy to identify critical cancer genes.