Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Blood. 2020 Mar 19;135(12):934-947. doi: 10.1182/blood.2019002639.
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.
成人 T 细胞白血病/淋巴瘤（ATL）是一种源自成熟 CD4+ T 淋巴细胞的高度侵袭性血液恶性肿瘤。在这里，我们展示了由 2 个致癌转录因子 IRF4 和 NF-κB 驱动的 ATL 细胞中的转录调控网络。对原发性 ATL 样本的基因表达谱分析表明，IRF4 基因在 ATL 细胞中的表达水平高于正常 T 细胞。染色质免疫沉淀测序分析显示，IRF4 结合区域在超增强子中比在典型增强子中更常见。发现 NF-κB 与 IRF4 结合的调节元件共同占据，并形成一个连贯的前馈环，共同调节参与 T 细胞功能和发育的基因。重要的是，IRF4 和 NF-κB 在 ATL 细胞中调节了几个与超增强子相关的癌症基因，包括 MYC、CCR4 和 BIRC3。BIRC3 的遗传抑制诱导 ATL 细胞生长抑制，暗示其作为 IRF4-NF-κB 转录网络下游的关键效应分子的作用。
