Feed-forward regulatory loop driven by IRF4 and NF-κB in adult T-cell leukemia/lymphoma
Regina Wan Ju Wong, Tze King Tan, Stella Amanda, Phuong Cao Thi Ngoc, Wei Zhong Leong, Shi Hao Tan, Kaori Asamitsu, Yurina Hibi, Ryuzo Ueda, Takashi Okamoto, Takashi Ishida, Shinsuke Iida, Takaomi Sanda
Abstract
Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive hematological malignancy derived from mature CD4+ T-lymphocytes. Here, we demonstrate the transcriptional regulatory network driven by 2 oncogenic transcription factors, IRF4 and NF-κB, in ATL cells. Gene expression profiling of primary ATL samples demonstrated that the IRF4 gene was more highly expressed in ATL cells than in normal T cells. Chromatin immunoprecipitation sequencing analysis revealed that IRF4-bound regions were more frequently found in super-enhancers than in typical enhancers. NF-κB was found to co-occupy IRF4-bound regulatory elements and formed a coherent feed-forward loop to coordinately regulate genes involved in T-cell functions and development. Importantly, IRF4 and NF-κB regulated several cancer genes associated with super-enhancers in ATL cells, including MYC, CCR4, and BIRC3. Genetic inhibition of BIRC3 induced growth inhibition in ATL cells, implicating its role as a critical effector molecule downstream of the IRF4-NF-κB transcriptional network.