Noncoding mutations cause super-enhancer retargeting resulting in protein synthesis dysregulation during B cell lymphoma progression
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Published:2023-12
Issue:12
Volume:55
Page:2160-2174
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ISSN:1061-4036
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Container-title:Nature Genetics
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language:en
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Short-container-title:Nat Genet
Author:
Leeman-Neill Rebecca J.ORCID, Song DongORCID, Bizarro Jonathan, Wacheul LudivineORCID, Rothschild Gerson, Singh SameerORCID, Yang Yang, Sarode Aditya Y.ORCID, Gollapalli KishoreORCID, Wu Lijing, Zhang WanweiORCID, Chen YiyunORCID, Lauring Max C., Whisenant D. Eric, Bhavsar Shweta, Lim Junghyun, Swerdlow Steven H.ORCID, Bhagat GovindORCID, Zhao QianORCID, Berchowitz Luke E., Lafontaine Denis L. J.ORCID, Wang JiguangORCID, Basu UttiyaORCID
Abstract
AbstractWhole-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.
Publisher
Springer Science and Business Media LLC
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