3D Genome Collapse Lymphoma Risk

3D Genome Collapse Linked to Lymphoma Risk, ASH 2025 Study Reveals

Cancer Stems From More Than Mutations — It Also Begins in the Cell's Architecture

Cancer stems not only from defective genes but also from a breakdown in the cell's structural design. It is akin to a city losing its transport links overnight, leaving neighbourhoods cut off from essential support. Inside the cell, this happens when the 3D DNA framework collapses.

ASH 2025 Presentation Highlights New Structural Cause of Lymphoma

Presenting at the 2025 American Society of Hematology (ASH) conference, Martin Rivas, Ph.D., of the Sylvester Comprehensive Cancer Centre at the University of Miami Miller School of Medicine, reported that even minor alterations in genome architecture may predispose individuals to lymphoma. This discovery provides an important shifts in how blood cancers may be interpreted and treated.

"We've long understood that mutations fuel cancer," Rivas explained. "But this study shows that architecture—how DNA folds—can be equally crucial. It's rather like misplacing the blueprint of a building halfway through construction."

AI-Powered Tools Reveal Weakening DNA Loops

By applying AI-powered analytics to vast datasets drawn from Hi-C maps, single-cell RNA sequencing and epigenetic profiling, the researchers identified a striking trend:

SMC3 or CTCF haploinsufficiency—where only part of the protein function is lost—does not dismantle the genome's entire 3D structure. Instead, it selectively weakens short-range enhancer-promoter loops, the crucial wiring that keeps tumour-suppressor genes such as Tet2, Kmt2d and Dusp4 switched on.

When these loops fail, B-cells reach a developmental "bottleneck" and cannot progress into plasma cells, leaving the door open for malignancy to take hold.

AI Shows How DNA Architecture Controls Cancer Risk

AI technologies enabled the team to weave together these complex data layers, exposing how shifts in genomic architecture can reverberate through gene expression and ultimately shape cell fate.

"This is precisely where computational biology excels," Rivas noted. "AI allowed us to detect patterns imperceptible to the human eye—showing how the loss of even a single gene copy can remodel the entire 3D landscape."

Clinical Impact Patients With Reduced SMC3 Levels Show Worse Outcomes

The implications reach far beyond theory. Patients with diffuse large B-cell lymphoma (DLBCL) who display reduced SMC3 levels tend to have poorer outcomes. This raises the possibility that genome architecture could serve as both a prognostic biomarker and a future therapeutic target. Rather than repairing mutations, emerging treatments may instead aim to restore proper looping—or replicate its function.

A New Frontier in Cancer Treatment — Repairing DNA Architecture

This study reshapes our understanding of cancer biology: the problem is not confined to the genetic code itself, but extends to the structural framework that supports it. By uncovering how architectural tumour suppression works, researchers can begin to investigate therapies designed to stabilize genome structure—opening an entirely new frontier in oncology.

"We're entering an era where treating cancer may involve repairing the architecture rather than merely patching up faulty genes," Rivas said. "That's genuine paradigm shift."

The City Analogy Why DNA Loops Matter

Return to the city analogy: when roads vanish, districts become cut off and daily life collapses. Inside a cell, the disappearance of DNA loops cuts off tumour suppressor genes from vital connections and cancer finds its opening. Restoring those links may ultimately be the key to keeping both the city, and the cell, alive.

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