Noncoding mutations cause super-enhancer retargeting resulting in protein synthesis dysregulation during B cell lymphoma progression

Rebecca J Leeman-Neill; Dong Song; Jonathan Bizarro; Ludivine Wacheul; Gerson Rothschild; Sameer Singh; Yang Yang; Aditya Y Sarode; Kishore Gollapalli; Lijing Wu; Wanwei Zhang; Yiyun Chen; Max C Lauring; D Eric Whisenant; Shweta Bhavsar; Junghyun Lim; Steven H Swerdlow; Govind Bhagat; Qian Zhao; Luke E Berchowitz; Denis L J Lafontaine; Jiguang Wang; Uttiya Basu

doi:10.1038/s41588-023-01561-1

Noncoding mutations cause super-enhancer retargeting resulting in protein synthesis dysregulation during B cell lymphoma progression

Nat Genet. 2023 Dec;55(12):2160-2174. doi: 10.1038/s41588-023-01561-1. Epub 2023 Dec 4.

Authors

Rebecca J Leeman-Neill^#^{1

2}, Dong Song^#^{3

4}, Jonathan Bizarro¹, Ludivine Wacheul⁵, Gerson Rothschild¹, Sameer Singh⁶, Yang Yang⁷, Aditya Y Sarode¹, Kishore Gollapalli¹, Lijing Wu¹, Wanwei Zhang¹, Yiyun Chen⁴, Max C Lauring¹, D Eric Whisenant¹, Shweta Bhavsar⁸, Junghyun Lim⁹, Steven H Swerdlow⁸, Govind Bhagat², Qian Zhao⁷, Luke E Berchowitz¹⁰, Denis L J Lafontaine⁵, Jiguang Wang^{11

12

13}, Uttiya Basu¹⁴

Affiliations

¹ Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA.
² Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA.
³ SIAT-HKUST Joint Laboratory of Cell Evolution and Digital Health, Shenzhen-Hong Kong Collaborative Innovation Research Institute, Shenzhen, China.
⁴ Division of Life Science, Department of Chemical and Biological Engineering, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
⁵ RNA Molecular Biology, Fonds de la Recherche Scientifique (F.R.S./FNRS), Université libre de Bruxelles (ULB), Biopark Campus, Gosselies, Belgium.
⁶ Institut für Medizinische Physik und Biophysik, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁷ State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China.
⁸ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁹ Department of Pharmacy, School of Pharmacy and Institute of New Drug Development, Jeonbuk National University, Jeonju, Republic of Korea.
¹⁰ Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA.
¹¹ SIAT-HKUST Joint Laboratory of Cell Evolution and Digital Health, Shenzhen-Hong Kong Collaborative Innovation Research Institute, Shenzhen, China. [email protected].
¹² Division of Life Science, Department of Chemical and Biological Engineering, and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong SAR, China. [email protected].
¹³ Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong SAR, China. [email protected].
¹⁴ Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA. [email protected].

^# Contributed equally.

Abstract

Whole-genome sequencing of longitudinal tumor pairs representing transformation of follicular lymphoma to high-grade B cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma) identified coding and noncoding genomic alterations acquired during lymphoma progression. Many of these transformation-associated alterations recurrently and focally occur at topologically associating domain resident regulatory DNA elements, including H3K4me3 promoter marks located within H3K27ac super-enhancer clusters in B cell non-Hodgkin lymphoma. One region found to undergo recurrent alteration upon transformation overlaps a super-enhancer affecting the expression of the PAX5/ZCCHC7 gene pair. ZCCHC7 encodes a subunit of the Trf4/5-Air1/2-Mtr4 polyadenylation-like complex and demonstrated copy number gain, chromosomal translocation and enhancer retargeting-mediated transcriptional upregulation upon lymphoma transformation. Consequently, lymphoma cells demonstrate nucleolar dysregulation via altered noncoding 5.8S ribosomal RNA processing. We find that a noncoding mutation acquired during lymphoma progression affects noncoding rRNA processing, thereby rewiring protein synthesis leading to oncogenic changes in the lymphoma proteome.

MeSH terms

Humans
Lymphoma* / genetics
Lymphoma, B-Cell* / genetics
Lymphoma, B-Cell* / pathology
Mutation
Regulatory Sequences, Nucleic Acid
Translocation, Genetic / genetics

Abstract

MeSH terms

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