小柯机器人

美国哥伦比亚大学Riccardo Dalla-Favera和Laura Pasqualucci共同合作近期取得重要研究进展，他们研究发现超级增强子的超突变改变了B细胞淋巴瘤中致癌基因的表达。这一研究成果2022年7月6日在线发表于《自然》杂志上。

研究人员表明92%的DLBCL个体样本中的活性超级增强子高度且特异性地超突变，显示出激活诱导的胞苷脱氨酶活性的特征，并且与编码B细胞发育调节因子和癌基因的基因相关。作为致癌相关性的证据，研究人员表明，与BCL6、BCL2和CXCR4原癌基因相连的高突变的超级增强子，会阻止转录抑制因子对相应靶基因的结合和转录下调，包括BLIMP1（靶向BCL6）和类固醇受体NR3C1（靶向BCL2和CXCR4）。选定突变的遗传校正恢复了阻遏物结合DNA、下调靶基因表达，并导致含有校正等位基因的细胞的反选择，表明对超级增强子突变的致癌依赖性。

这种普遍存在的超级增强子突变机制揭示了一组主要的基因损伤突变使基因表达失调，这扩大了已知癌基因在DLBCL发病机制中的参与，并确定了与治疗相关的新的失调基因靶标。

据了解，弥漫性大B细胞淋巴瘤(DLBCL)是最常见的B细胞非霍奇金淋巴瘤，约40%的患者仍无法治愈。对编码基因组的测序发现了几种在这种疾病中发生改变的基因和相关途径，包括潜在的治疗靶点。然而，DLBCL的非编码基因组在很大程度上仍未被探索。

附：英文原文

Title: Super-enhancer hypermutation alters oncogene expression in B cell lymphoma

Author: Bal, Elodie, Kumar, Rahul, Hadigol, Mohammad, Holmes, Antony B., Hilton, Laura K., Loh, Jui Wan, Dreval, Kostiantyn, Wong, Jasper C. H., Vlasevska, Sofija, Corinaldesi, Clarissa, Soni, Rajesh Kumar, Basso, Katia, Morin, Ryan D., Khiabanian, Hossein, Pasqualucci, Laura, Dalla-Favera, Riccardo

Issue&Volume: 2022-07-06

Abstract: 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 targets1,2,3,4,5. 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.

DOI: 10.1038/s41586-022-04906-8

Source: https://www.nature.com/articles/s41586-022-04906-8

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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