Super-enhancer hypermutation alters oncogene expression in B cell lymphoma

Bal, Elodie and Kumar, Rahul and Hadigol, Mohammad and et al, . (2022) Super-enhancer hypermutation alters oncogene expression in B cell lymphoma. Nature. ISSN 0028-0836

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Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common B cell non-Hodgkin lymphoma and remains incurable in around 40% of patients. Efforts to sequence the coding genome identified several genes and pathways that are altered in this disease, including potential therapeutic targets1–5. However, the non-coding genome of DLBCL remains largely unexplored. Here we show that active super-enhancers are highly and specifically hypermutated in 92% of samples from individuals with DLBCL, display signatures of activation-induced cytidine deaminase activity, and are linked to genes that encode B cell developmental regulators and oncogenes. As evidence of oncogenic relevance, we show that the hypermutated super-enhancers linked to the BCL6, BCL2 and CXCR4 proto-oncogenes prevent the binding and transcriptional downregulation of the corresponding target gene by transcriptional repressors, including BLIMP1 (targeting BCL6) and the steroid receptor NR3C1 (targeting BCL2 and CXCR4). Genetic correction of selected mutations restored repressor DNA binding, downregulated target gene expression and led to the counter-selection of cells containing corrected alleles, indicating an oncogenic dependency on the super-enhancer mutations. This pervasive super-enhancer mutational mechanism reveals a major set of genetic lesions deregulating gene expression, which expands the involvement of known oncogenes in DLBCL pathogenesis and identifies new deregulated gene targets of therapeutic relevance. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

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IITH Creators:

IITH Creators	ORCiD
Kumar, Rahul	https://orcid.org/0000-0002-6927-5390

Item Type:

Article

Additional Information:

We thank A. Ciccia and T. S. Nambiar for their advice on the design of CRISPR–Cas9 experiments; K. R. Loeb and L. A. Loeb for sharing the BCL6 mutation data in memory B cells prior to publication; A. Singh for help with the multivariate analysis; and A. A. Ferrando, U. Klein and R. Küppers for reading the manuscript. This study was supported by NIH grants R35-CA210105 (to R.D.-F.), R01-CA172492 (to L.P.) and R01-CA233662 (to H.K.); an AstraZeneca Scholar Award (to R.D.-F. and L.P.); a Herbert Irving Comprehensive Cancer Center (HICCC) VELOCITY award (to L.P. and R.D.-F.); and a Translational Grant from the V Foundation (T2019-012) (to H.K.). The study was also funded in part through the NIH/NCI Cancer Center Support Grant P30-CA13696 (HICCC) and P30-CA072720 (Rutgers Cancer Institute of New Jersey), and used the resources of the HICCC CCTI Flow Cytometry Core Facility, the Molecular Pathology Shared Resource and the JP Sulzberger Genome Center at Columbia University Irving Medical Center, as well as the Biomedical Informatics Shared Resource at Rutgers Cancer Institute of New Jersey. E.B. was an AACR-AstraZeneca Lymphoma Research Fellow, and C.C. is supported by a Lymphoma Research Foundation fellowship. K.D. was supported by grant 1P01CA229100 from the National Cancer Institute (to D. W. Scott). L.P. is on leave from the University of Perugia Medical School, Perugia, Italy. The results published here are in whole or in part based on data generated by the Cancer Genome Characterization Initiative (CGCI) (phs000235), non-Hodgkin Lymphoma, developed by the NCI and available at https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000235.v14.p2 and https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000527.v3.p1 . Information about CGCI projects can be found online ( https://ocg.cancer.gov/programs/cgci ). We also acknowledge the members of the ICGC MALY-DE project ( https://dcc.icgc.org ) and the European Genome–Phenome Archive ( https://ega-archive.org ) for providing access to their datasets. All data were used according to the data use agreements.

Uncontrolled Keywords:

Diffuse large B cell lymphoma (DLBCL), B cell non-Hodgkin lymphoma, potential therapeutic targets1–5,steroid receptor NR3C1 (targeting BCL2 and CXCR4).

Subjects:

Others > Medicine
Others > Microbiology
Others > Biochemistry
Others > Biotechnology
Others > Cellular biology

Divisions:

Department of Biotechnology

Depositing User:

. LibTrainee 2021

Date Deposited:

18 Jul 2022 11:24

Last Modified:

18 Jul 2022 11:24

URI:

http://raiithold.iith.ac.in/id/eprint/9771