Super-enhancer hypermutation alters oncogene expression in B cell lymphoma

Area of Science:

• Genomics
• Cancer Biology
• Hematology

Background:

• Diffuse large B cell lymphoma (DLBCL) is the most prevalent B cell non-Hodgkin lymphoma, with approximately 40% of patients remaining incurable.
• While the coding genome of DLBCL has been extensively studied, the non-coding genome remains largely unexplored.
• Identifying novel genetic alterations and therapeutic targets is crucial for improving DLBCL treatment outcomes.

Purpose of the Study:

• To investigate the role of the non-coding genome, specifically super-enhancers, in the pathogenesis of DLBCL.
• To determine if super-enhancers are altered in DLBCL and if these alterations have functional consequences.
• To identify potential new therapeutic targets within the non-coding genome of DLBCL.

Main Methods:

• Analysis of active super-enhancers in DLBCL patient samples using whole-genome sequencing.
• Assessment of mutational signatures, including activation-induced cytidine deaminase activity.
• Functional studies to evaluate the impact of super-enhancer mutations on gene regulation and oncogene expression.
• Genetic correction of mutations to assess oncogenic dependency.

Main Results:

• Active super-enhancers are specifically and highly hypermutated in 92% of DLBCL samples.
• These hypermutated super-enhancers display signatures of activation-induced cytidine deaminase activity.
• Mutations in super-enhancers linked to BCL6, BCL2, and CXCR4 prevent transcriptional repressor binding, leading to oncogene upregulation.
• Genetic correction of these mutations restored repressor binding, downregulated target genes, and resulted in counter-selection of mutated alleles, indicating oncogenic dependency.

Conclusions:

• A pervasive super-enhancer mutational mechanism contributes to DLBCL pathogenesis by deregulating gene expression.
• These findings expand the known involvement of oncogenes in DLBCL and identify novel deregulated gene targets.
• Super-enhancer mutations represent a significant class of genetic lesions in DLBCL with potential therapeutic relevance.