Cancer research is entering a new frontier as scientists explore the vital role of DNA architecture in lymphoma development. A recent study presented at the 2025 American Society of Hematology meeting by Martin Rivas, Ph.D., a researcher at Sylvester Comprehensive Cancer Center affiliated with the University of Miami Miller School of Medicine, indicates that even small disruptions in the three-dimensional structure of DNA can increase the risk of developing lymphoma.
The study, titled “SMC3 and CTCF Haploinsufficiency Drive Lymphoid Malignancy via 3D Genome Dysregulation and Disruption of Tumor Suppressor Enhancer-Promoter Loops,” sheds light on a novel concept termed architectural tumor suppression. Proteins such as SMC3 and CTCF are not merely structural components; they play a critical role in preventing cancer by maintaining essential loops that connect gene enhancers to their corresponding promoters. A reduction in these proteins can lead to the loss of these loops, effectively silencing vital tumor suppressor genes.
Dr. Rivas explains the significance of this work: “We’ve long known that mutations drive cancer. But this research shows that architecture—the way DNA folds—can be just as important. It’s like losing the blueprint for a building while construction is underway.”
The research team utilized artificial intelligence (AI) to analyze extensive datasets derived from Hi-C mapping, single-cell RNA sequencing, and epigenetic profiles. This approach revealed that haploinsufficiency of SMC3 or CTCF does not completely disrupt the genome’s structure. Instead, it selectively erodes the short-range enhancer-promoter loops that are crucial for the activity of tumor suppressor genes, including Tet2, Kmt2d, and Dusp4.
As a result, B cells encounter a “decision bottleneck,” preventing their maturation into plasma cells, which fosters an environment conducive to malignancy. AI tools played a pivotal role in this study, allowing the researchers to discern patterns that would otherwise remain hidden, demonstrating how the loss of a single gene copy can reshape the entire three-dimensional landscape of the genome.
Furthermore, the implications of these findings are significant for clinical practice. Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) who exhibit lower levels of SMC3 expression tend to have poorer outcomes. This correlation suggests that genome architecture could serve as a potential biomarker for prognosis and may even become a target for new therapeutic strategies. Rather than merely addressing genetic mutations, future treatments might focus on restoring proper genomic looping or simulating its effects.
This research fundamentally reframes our understanding of cancer biology. It emphasizes that the genetic code is not the sole factor in cancer development; the structural integrity that supports it is equally vital. By focusing on architectural tumor suppression, scientists can investigate therapies aimed at stabilizing genome structure, paving the way for innovative approaches in oncology.
Dr. Rivas articulates this shift in perspective: “We’re entering an era where cancer treatment could mean repairing architecture, not just fixing broken genes. That’s a paradigm shift.” This evolving understanding underscores the importance of maintaining the cellular infrastructure that supports life, both in cities and within our bodies. When the connections within the DNA architecture are compromised, the risk of cancer increases, highlighting the need for a comprehensive approach to cancer research and treatment.
