增强子
生物
胞苷脱氨酶
基因
体细胞突变
遗传学
癌症研究
活化诱导(胞苷)脱氨酶
基因表达调控
基因表达
B细胞
抗体
作者
Élodie Bal,Rahul Kumar,Mohammad Hadigol,Antony B. Holmes,Laura K. Hilton,Jui Wan Loh,Kostiantyn Dreval,Jasper Wong,Sofija Vlasevska,Clarissa Corinaldesi,Rajesh Kumar Soni,Katia Basso,Ryan D. Morin,Hossein Khiabanian,Laura Pasqualucci,Riccardo Dalla‐Favera
出处
期刊:Nature
[Springer Nature]
日期:2022-07-06
卷期号:607 (7920): 808-815
被引量:61
标识
DOI:10.1038/s41586-022-04906-8
摘要
Diffuse large B cell lymphoma (DLBCL) is the most common B cell non-Hodgkin lymphoma and remains incurable in around 40% of patients. Efforts to sequence the coding genome identified several genes and pathways that are altered in this disease, including potential therapeutic targets1–5. However, the non-coding genome of DLBCL remains largely unexplored. Here we show that active super-enhancers are highly and specifically hypermutated in 92% of samples from individuals with DLBCL, display signatures of activation-induced cytidine deaminase activity, and are linked to genes that encode B cell developmental regulators and oncogenes. As evidence of oncogenic relevance, we show that the hypermutated super-enhancers linked to the BCL6, BCL2 and CXCR4 proto-oncogenes prevent the binding and transcriptional downregulation of the corresponding target gene by transcriptional repressors, including BLIMP1 (targeting BCL6) and the steroid receptor NR3C1 (targeting BCL2 and CXCR4). Genetic correction of selected mutations restored repressor DNA binding, downregulated target gene expression and led to the counter-selection of cells containing corrected alleles, indicating an oncogenic dependency on the super-enhancer mutations. This pervasive super-enhancer mutational mechanism reveals a major set of genetic lesions deregulating gene expression, which expands the involvement of known oncogenes in DLBCL pathogenesis and identifies new deregulated gene targets of therapeutic relevance. Active super-enhancers are highly and specifically hypermutated in 92% of diffuse large B cell lymphoma samples and display signatures of activation-induced cytidine deaminase activity, leading to the dysregulation of genes encoding B cell developmental regulators and oncogenes.
科研通智能强力驱动
Strongly Powered by AbleSci AI