Non-coding regulatory mutations in Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) remains incurable in ~40 percent of patients. Coding-genome sequencing efforts identified several genes/pathways altered in this disease, including new therapeutic targets. However, the non-coding genome of DLBCL remains unexplored despite emerging evidence indicating the occurrence of recurrent mutations contributing to tumorigenesis in other tumor types. This project aims at identifying the landscape of functional non-coding mutations deregulating gene expression in DLBCL. Preliminary analysis indicates that the AID-mediated aberrant somatic hypermutation mechanism, which involves >50 percent of DLBCL, specifically recognizes gene-body enhancers/superenhancers (E/SE) of multiple proto-oncogenes, suggesting that this process can cause extensive gene deregulation. Using whole-genome sequencing and RNA-seq analysis of DLBCL cells, she will identify non-coding mutations that lead to E/SE dysregulation, as documented by ChIP-seq of histone modification marks. Candidate lesions will be functionally dissected for their specific effect on gene transcription. The results of this project are expected to identify novel mechanisms of DLBCL pathogenesis, thus revealing novel targets for therapeutic intervention.