Genomics of Diffuse Large B Cell Lymphoma: pervasive role of super-enhancer hypermutation in dysregulating oncogene expression
Riccardo Dalla-Favera
MDColumbia University Medical Center
Project Term: October 1, 2023 - September 30, 2026
We recently identified a pervasive, pathogenically relevant mutational mechanism that targets super-enhancers (SE) in DLBCL, leading to target gene deregulation. Here we will dissect the mechanistic role of 3 highly recurrent hotspots in the BCL6, BTG2 and CXCR4 SEs in driving lymphomagenesis and tumor dependency in vitro and in vivo using novel mouse models. These studies will significantly transform our understanding of DLBCL and identify novel therapeutic targets.
Diffuse Large B Cell Lymphoma (DLBCL), the most common hematologic cancer, is incurable in ~30% of patients. One barrier to effective cures is the remarkable heterogeneity of these tumors, which encompass as many as 8 genetic subtypes characterized by distinct patterns of DNA alterations and different response to therapy, but also include a large number of cases that cannot be unequivocally classified. Following on the hypothesis that this may be due to DNA errors in the unexplored non-coding regulatory portion of the genome (i.e. the DNA regions that control the expression of cell-specific genes), we recently found that 97% of DLBCL cases show an aberrant somatic hypermutation (aSHM) activity targeting specific regions called super-enhancers (SEs), which represent the main switch to dictate the cell identity and cell fate. These mutated SEs control the expression of multiple genes, including well-known lymphoma drivers, and we demonstrated that specific mutations hijack their activity, causing the inappropriate expression of the linked gene. Moreover, tumors are dependent on the presence of these mutations for their fitness and survival, indicating a key role in the disease and a potential Achille’s heel for the tumor (Bal et al., Nature 2022). The overall goal of this research program will be to identify how mutations in 3 recurrently mutated SEs deregulate gene expression and facilitate the development of lymphoma, including the construction of mouse models that could serve for the pre-clinical testing of new precision therapies. We anticipate that this new layer of genetic alterations will identify novel mechanisms of dysregulation for known and new oncogenes and pathways, with implications for the clinical management of DLBCL patients.