Super-enhancer hypermutation alters oncogene expression in B cell lymphoma

Elodie Bal, Rahul Kumar, Mohammad Hadigol, Antony B. Holmes, Laura K. Hilton, Jui Wan Loh, Kostiantyn Dreval, Jasper C. H. Wong, Sofija Vlasevska, Clarissa Corinaldesi, Rajesh Kumar Soni, Katia Basso, Ryan D. Morin, Hossein Khiabanian, Laura Pasqualucci () and Riccardo Dalla-Favera ()
Additional contact information
Elodie Bal: Columbia University
Rahul Kumar: Columbia University
Mohammad Hadigol: Rutgers University
Antony B. Holmes: Columbia University
Laura K. Hilton: BC Cancer Research Centre
Jui Wan Loh: Rutgers University
Kostiantyn Dreval: Simon Fraser University
Jasper C. H. Wong: BC Cancer Research Centre
Sofija Vlasevska: Columbia University
Clarissa Corinaldesi: Columbia University
Rajesh Kumar Soni: Columbia University
Katia Basso: Columbia University
Ryan D. Morin: Simon Fraser University
Hossein Khiabanian: Rutgers University
Laura Pasqualucci: Columbia University
Riccardo Dalla-Favera: Columbia University

Nature, 2022, vol. 607, issue 7920, 808-815

Abstract: 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 targets1–5. 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.

Date: 2022
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DOI: 10.1038/s41586-022-04906-8

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