Broken DNA Loops Trigger Lymphoma Development

New study shows DNA’s 3D structure helps prevent lymphoma by keeping tumor suppressor genes active.

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Cancer isn’t just driven by genetic mutations - it also stems from structural breakdowns within the genome. Picture a city where roads vanish, cutting off communities from vital resources. That’s what happens at the cellular level when the three-dimensional structure of DNA begins to unravel.

The recent study, presented at the 2025 American Society of Hematology (ASH) meeting by Martin Rivas, Ph.D., reveals that subtle disruptions in genome architecture can predispose individuals to lymphoma.

This finding is a fresh perspective on the understanding and treatment of blood cancers, suggesting that the three-dimensional structure of DNA, not just genetic mutations, plays a critical role in cancer development.

The research looks at the concept of architectural tumor suppression. Proteins such as SMC3 and CTCF are responsible for organizing DNA. But they also prevent cancer by maintaining loops that connect gene regulatory elements called enhancers to the genes they control, known as promoters.

The partial loss of these proteins can lead to the disappearance of these loops, which in turn silences crucial tumor suppressor genes.

We’ve long known that mutations drive cancer. 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 underway.

Dr. Martin Rivas, Assistant Professor, Biochemistry and Molecular Biology, Miller School

The research team used AI-driven analytics to interpret extensive datasets from Hi-C maps, single-cell RNA sequencing, and epigenetic profiles. This analysis uncovered a significant pattern.

Partial loss of SMC3 or CTCF, known as haploinsufficiency, does not disrupt the entire genome structure. Instead, it weakens short-range enhancer-promoter loops. These loops are essential for maintaining the activity of tumor suppressor genes, including Tet2, Kmt2d, and Dusp4.

When these loops are compromised, B cells encounter a developmental obstacle. They fail to mature into plasma cells, creating an environment conducive to malignancy. Artificial intelligence tools played a central role in integrating these complex data layers. They revealed how alterations in genome architecture impact gene expression and cell fate.

This is where computational biology shines. AI allowed us to see patterns invisible to the human eye, and how losing just one copy of a gene reshapes the entire 3D landscape.

Dr. Martin Rivas, Assistant Professor, Biochemistry and Molecular Biology, Miller School

These findings have a practical impact. Patients with diffuse large B-cell lymphoma (DLBCL) who exhibit lower SMC3 expression tend to have poorer outcomes. This suggests that genome architecture could serve as a biomarker for prognosis and potentially as a therapeutic target.

Future treatments might focus on restoring proper DNA looping or mimicking its effects, rather than solely addressing genetic mutations.

This research redefines cancer biology. It highlights that cancer development is not solely about the genetic code but also about the structural framework that supports it. By understanding architectural tumor suppression, scientists can explore novel therapies aimed at stabilizing genome structure, opening a new frontier in oncology.

Reference

Smith, M. (2025) ‘When DNA’s architecture goes awry: a new frontier in lymphoma research’, University of Miami Miller School of Medicine News, 6 December.