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

par Leeman-Neill, Rebecca;Song, Dong;Bizarro, Jonathan;Wacheul, Ludivine ;Rothschild, Gerson;Singh, Sameer;Yang, Yang;Sarode, Aditya;Gollapalli, Kishore;Wu, Lijing;Zhang, Wanwei;Chen Y, Y;Lauring, Max;Whisenant, Eric;Bhavsar, Shweta;Lim, Jun;Swerdlow, Steven;Bhagat, Govind;Zhao, Qian;Berchowitz, Luke;Lafontaine, Denis ;Wang, Jiguang;Basu, Uttiya
Référence Nature genetics, 55, 12, page (2160-2174)
Publication Publié, 2023-12-01

Article révisé par les pairs

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Résumé :

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.