Description:

The Simpson Querrey Institute for Epigenetics presents:

Riccardo Dalla-Favera, MD

Uris Professor of Clinical Medicine; Professor, Pathology and Cell Biology;
Professor, Genetics & Development; Professor, Microbiology & Immunology
Director, Institute for Cancer Genetics, Columbia University, NYC

“Genomics of B Cell Lymphoma: Role of Super-Enhancer Hypermutation”

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma and remains incurable in ~40% of patients. Coding-genome sequencing efforts identified several genes/pathways altered in this disease, including new potential therapeutic targets. However, the non-coding genome of DLBCL remains largely unexplored. We found that active super-enhancers (SEs) are highly and specifically hypermutated in 92% of DLBCL samples. Hypermutation is due to the activity of activation-induced cytidine deaminase (AICDA), which normally targets Immunoglobulin genes.  Hypermutated SE are linked to genes encoding B-cell developmental regulators and oncogenes. As evidence of oncogenic relevance, we show that the hypermutated SEs linked to the BCL6, BCL2, and CXCR4 proto-oncogenes prevent the binding and transcriptional downregulation of the corresponding target gene by specific transcriptional repressors. Genetic correction of selected mutations restored repressor DNA-binding, downregulated target gene expression, and led to the counter-selection of cells harboring corrected alleles, indicating oncogenic dependency from the SE mutations. This pervasive SE mutational mechanism reveals a new 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. The functional approach used for these studies may find general application in investigating mutational events in regulatory domains in other tumors and in germ-line DNA. (Bal et al., Nature, in press)