Cancer researchers have found that disruptions in the 3D structure of DNA, not just genetic mutations, can contribute to the development of lymphoma. The study was presented on December 6 at the 2025 American Society of Hematology (ASH) meeting by Martin Rivas, Ph.D., a researcher at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine.
The research focused on proteins SMC3 and CTCF, which help maintain DNA loops that connect enhancers—regions controlling gene activity—to promoters—the start sites for genes. According to the study titled "SMC3 and CTCF Haploinsufficiency Drive Lymphoid Malignancy via 3D Genome Dysregulation and Disruption of Tumor Suppressor Enhancer-Promoter Loops," even a partial loss of these proteins leads to fewer loops. This causes tumor suppressor genes such as Tet2, Kmt2d, and Dusp4 to be silenced.
"We've long known that mutations drive cancer," said Rivas. "But this work shows that architecture—the way DNA folds—can be just as important. It's like losing the blueprint for a building while construction is under way."
Researchers used artificial intelligence tools to analyze data from Hi-C maps, single-cell RNA sequencing, and epigenetic profiles. These methods allowed them to see how changes in genome architecture affect gene expression and cell development.
"This is where computational biology shines," Rivas added. "AI allowed us to see patterns invisible to the human eye—how losing just one copy of a gene reshapes the entire 3D landscape."
The study found that when enhancer-promoter loops are lost due to reduced SMC3 or CTCF levels, B-cells cannot mature properly into plasma cells. This failure creates conditions favorable for lymphoma development.
In patients with diffuse large B-cell lymphoma (DLBCL), those with lower SMC3 expression tend to have worse outcomes. The researchers suggest that assessing genome architecture could become useful for prognosis or therapy in blood cancers. Future treatments might focus on restoring proper DNA looping rather than only correcting mutations.
"We're entering an era where cancer treatment could mean repairing architecture, not just fixing broken genes," said Rivas. "That's a paradigm shift."
The findings highlight a new approach in cancer research: focusing on both genetic sequences and the physical structure supporting them may lead to new therapeutic strategies.
