Posted: Wednesday, October 12, 2022
The results of a study published in Nature suggest that mutations in the noncoding genome of diffuse large B-cell lymphoma (DLBCL) may lead to functional consequences that contribute to tumorigenesis—specifically, somatic hypermutations in super-enhancers. In fact, most samples from individuals with DLBCL (92%) contained active super-enhancers that were highly hypermutated. “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,” stated Elodie Bal, PhD, and Riccardo Dalla-Favera, MD, of the Institute for Cancer Genetics, Columbia University, New York, and colleagues.
Analysis revealed that active super-enhancers are the major target of pervasive cytidine deaminase–mediated hypermutagenesis and display signatures of activation-induced cytidine deaminase activity. Active super-enhancers are also linked to genes that encode B-cell transcriptional regulators and oncogenes that are involved in germinal center biology and malignant transformation.
Several proto-oncogenes were identified as targets of super-enhancer hypermutation, including BCL6, BCL2, and CXCR4. These 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).
The study authors found that genetic correction of selected mutations restored repressor DNA binding, downregulated target gene expression, and led to the counter-selection of cells containing corrected alleles—suggesting an oncogenic dependency on the super-enhancer mutations. “We anticipate that this new layer of genetic alterations will identify mechanisms of dysregulation for known oncogenes, as well as new dysregulated genes and pathways, with implications for precision classification and therapeutic targeting of DLBCL,” they concluded.
Disclosure: For full disclosures of the study authors, visit www.nature.com.