A study by researchers at Columbia and the Hong Kong University of Science and Technology is helping to clarify how low-grade lymphoma changes as it develops into a more aggressive tumor, which could lead to the development of new treatments.
Though often incurable, many low-grade B-cell lymphomas are slow to develop and not life-threatening. Among some patients, however, the tumors transform into more aggressive lymphomas and pose a greater threat.
The transformation into more aggressive disease is thought to be assisted by a protein called AID that creates mutations throughout the B-cell genome. But the features and consequences of many of these mutations remain hidden.
To better understand how AID changes the genome and transforms lymphoma, a team led by Columbia researchers Rebecca Leeman-Neill, MD, PhD, and Uttiya Basu, PhD, and their HKUST collaborators, Dong Song and Jiguang Wang, PhD, tapped into 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 carry out whole genome sequencing of each tumor to track the mutations that accrued during transformation.
The genomic data revealed that transforming mutations were concentrated in noncoding, superenhancer-embedded promoter regions of many genes and altered gene expression in lymphomas in unexpected ways.
"We expected mutations in these regions to affect the transcription of genes normally controlled by the mutated promoters, but we also found that the enhancer-promoter interactions were rewired, affecting expression of other neighboring genes," Leeman-Neill says.
Illustration provided by Rebecca Leeman-Neill.
The researchers investigated the consequences of one particularly common transformation-associated mutation, in the PAX5 promoter, which resulted in rewiring of enhancer-promoter interactions, to turn on the ZCCHC7 gene. Those changes altered ribosome biogenesis, leading to widespread changes in protein synthesis in lymphoma cells, including a decline in the synthesis of DNA repair proteins, tumor suppressors, and proteins targeted by currently available therapeutics.
The findings also suggest that enhancer retargeting is widespread during lymphoma progression.
"These changes may reveal potential opportunities for treating aggressive lymphomas or even preventing their development," Leeman-Neill says
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Rebecca Leeman-Neill, MD, PhD is assistant professor of pathology & cell biology at Columbia University Vagelos College of Physicians and Surgeons.
Uttiya Basu, PhD, is professor of microbiology & immunology at Columbia University Vagelos College of Physicians and Surgeons.
The Columbia researchers were supported by the NIH (grants R01AI099195, RO1AI143897, R01AI134988, T32AI148099, and T32CA265828) and the U.S. Department of Defense (W81XWH-18-1-0394).
All co-authors are: Rebecca J. Leeman-Neill (Columbia), Dong Song (Shenzhen-Hong Kong Collaborative Innovation Research Institute and Hong Kong University of Science and Technology), Jonathan Bizarro (Columbia), Ludivine Wacheul (Université libre de Bruxelles), Gerson Rothschild (Columbia), Sameer Singh (Charité-Universitätsmedizin Berlin), Yang Yang (Hong Kong Polytechnic University), Aditya Y. Sarode (Columbia), Kishore Gollapalli (Columbia), Lijing Wu (Columbia), Wanwei Zhang (Columbia), Yiyun Chen (Hong Kong University of Science and Technology), Max C. Lauring (Columbia), D. Eric Whisenant (Columbia), Shweta Bhavsar (University of Pittsburgh), Junghyun Lim (Jeonbuk National University), Steven H. Swerdlow (University of Pittsburgh), Govind Bhagat, Qian Zhao (Hong Kong Polytechnic University), Luke E. Berchowitz (Columbia), Denis L. J. Lafontaine (Université libre de Bruxelles), Jiguang Wang (Shenzhen-Hong Kong Collaborative Innovation Research Institute, Hong Kong University of Science and Technology, and Hong Kong Center for Neurodegenerative Diseases), and Uttiya Basu (Columbia).
The authors declare no competing interests.
