Genomic data sheds light on how lymphoma can become deadly

A study led by researchers at Columbia and the Hong Kong University of Science and Technology helps clarify how low-grade lymphoma progresses as it turns into a more aggressive tumor, which could lead to the development of new treatments.

The results are published in the journal Natural genetics.

Although often incurable, many low-grade B-cell lymphomas grow slowly and are not life-threatening. In some patients, however, the tumors develop into more aggressive lymphomas and pose a greater threat.

The transformation into a more aggressive disease is thought to be facilitated by a protein called AID that creates mutations throughout the genome of B cells. But the characteristics and consequences of many of these mutations remain hidden.

To better understand how AID modifies the genome and transforms lymphoma, a team led by Columbia researchers Rebecca Leeman-Neill, MD, Ph.D., and Uttiya Basu, Ph.D., and their collaborators at HKUST, Dong Song and Jiguang Wang, Ph.D., leveraged a unique collection of tumor samples from patients whose follicular lymphoma transformed into a much more aggressive type called double-hit lymphoma.

Using samples collected at different times during the patients’ disease progression, the team was able to perform whole genome sequencing of each tumor to track mutations accumulated during transformation.

Genomic data revealed that transforming mutations were concentrated in noncoding promoter regions and integrated into superenhancers of many genes and changed gene expression in lymphomas in unexpected ways.

“We expected that mutations in these regions would affect the transcription of genes normally controlled by the mutated promoters, but we also found that enhancer-promoter interactions were rewired, affecting the expression of other neighboring genes,” explains Leeman-Neill.

The researchers studied the consequences of a particularly common transformation-associated mutation, in the PAX5 promoter, which resulted in rewiring of enhancer-promoter interactions, to activate the ZCCHC7 gene. These changes altered ribosome biogenesis, leading to widespread changes in protein synthesis in lymphoma cells, including decreased synthesis of DNA repair proteins, tumor suppressors, and proteins targeted by treatments. currently available.

The results also suggest that enhancer retargeting is prevalent during lymphoma progression.

“These changes could reveal potential opportunities to treat aggressive lymphomas or even prevent their development,” says Leeman-Neill.