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

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. BerchowitzDenis L.J. Lafontaine, Jiguang Wang, Uttiya Basu

Research output: Journal article publication › Journal article › Academic research › peer-review

8 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2160-2174
Number of pages	15
Journal	Nature Genetics
Volume	55
DOIs	https://doi.org/10.1038/s41588-023-01561-1
Publication status	Published - 4 Dec 2023

ASJC Scopus subject areas

Genetics

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10.1038/s41588-023-01561-1

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Leeman-Neill, R. J., Song, D., Bizarro, J., Wacheul, L., Rothschild, G., Singh, S., Yang, Y., Sarode, A. Y., Gollapalli, K., Wu, L., Zhang, W., Chen, Y., Lauring, M. C., Whisenant, D. E., Bhavsar, S., Lim, J., Swerdlow, S. H., Bhagat, G., Zhao, Q., ... Basu, U. (2023). Noncoding mutations cause super-enhancer retargeting resulting in protein synthesis dysregulation during B cell lymphoma progression. Nature Genetics, 55, 2160-2174. https://doi.org/10.1038/s41588-023-01561-1

@article{494541a76ee442819403405cdc60e3ee,

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

day = "4",

doi = "10.1038/s41588-023-01561-1",

language = "English",

volume = "55",

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Leeman-Neill, RJ, Song, D, Bizarro, J, Wacheul, L, Rothschild, G, Singh, S, Yang, Y, Sarode, AY, Gollapalli, K, Wu, L, Zhang, W, Chen, Y, Lauring, MC, Whisenant, DE, Bhavsar, S, Lim, J, Swerdlow, SH, Bhagat, G, Zhao, Q, Berchowitz, LE, Lafontaine, DLJ, Wang, J & Basu, U 2023, 'Noncoding mutations cause super-enhancer retargeting resulting in protein synthesis dysregulation during B cell lymphoma progression', Nature Genetics, vol. 55, pp. 2160-2174. https://doi.org/10.1038/s41588-023-01561-1

TY - JOUR

T1 - Noncoding mutations cause super-enhancer retargeting resulting in protein synthesis dysregulation during B cell lymphoma progression

AU - Leeman-Neill, Rebecca J.

AU - Song, Dong

AU - Bizarro, Jonathan

AU - Wacheul, Ludivine

AU - Rothschild, Gerson

AU - Singh, Sameer

AU - Yang, Yang

AU - Sarode, Aditya Y.

AU - Gollapalli, Kishore

AU - Wu, Lijing

AU - Zhang, Wanwei

AU - Chen, Yiyun

AU - Lauring, Max C.

AU - Whisenant, D. Eric

AU - Bhavsar, Shweta

AU - Lim, Junghyun

AU - Swerdlow, Steven H.

AU - Bhagat, Govind

AU - Zhao, Qian

AU - Berchowitz, Luke E.

AU - Lafontaine, Denis L.J.

AU - Wang, Jiguang

AU - Basu, Uttiya

PY - 2023/12/4

Y1 - 2023/12/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85178490498&partnerID=8YFLogxK

U2 - 10.1038/s41588-023-01561-1

DO - 10.1038/s41588-023-01561-1

M3 - Journal article

C2 - 38049665

AN - SCOPUS:85178490498

SN - 1061-4036

VL - 55

SP - 2160

EP - 2174

JO - Nature Genetics

JF - Nature Genetics

ER -

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

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