Dataset Information

Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma.

ABSTRACT: Most B cell lymphomas originate from B cells that have germinal center (GC) experience and bear chromosome translocations and numerous point mutations. GC B cells remodel their immunoglobulin (Ig) genes by somatic hypermutation (SHM) and class switch recombination (CSR) in their Ig genes. Activation Induced Deaminase (AID) initiates CSR and SHM by generating U:G mismatches on Ig DNA that can then be processed by Uracyl-N-glycosylase (UNG). AID promotes collateral damage in the form of chromosome translocations and off-target SHM, however, the exact contribution of AID activity to lymphoma generation and progression is not completely understood. Here we show using a conditional knock-in strategy that AID supra-activity alone is not sufficient to generate B cell transformation. In contrast, in the absence of UNG, AID supra-expression increases SHM and promotes lymphoma. Whole exome sequencing revealed that AID heavily contributes to lymphoma SHM, promoting subclonal variability and a wider range of oncogenic variants. Thus, our data provide direct evidence that UNG is a brake to AID-induced intratumoral heterogeneity and evolution of B cell lymphoma.

SUBMITTER: Delgado P

PROVIDER: S-EPMC7790409 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma.

Delgado Pilar P Álvarez-Prado Ángel F ÁF Marina-Zárate Ester E Sernandez Isora V IV Mur Sonia M SM de la Barrera Jorge J Sanchez-Cabo Fátima F Cañamero Marta M de Molina Antonio A Belver Laura L de Yébenes Virginia G VG Ramiro Almudena R AR

PLoS genetics 20201223 12

Most B cell lymphomas originate from B cells that have germinal center (GC) experience and bear chromosome translocations and numerous point mutations. GC B cells remodel their immunoglobulin (Ig) genes by somatic hypermutation (SHM) and class switch recombination (CSR) in their Ig genes. Activation Induced Deaminase (AID) initiates CSR and SHM by generating U:G mismatches on Ig DNA that can then be processed by Uracyl-N-glycosylase (UNG). AID promotes collateral damage in the form of chromosome ...[more]

PMID: 33362210

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Project description:Emerging evidence highlights the potential impact of intratumoral microbiota on cancer. However, the microbial composition and function in glioma remains elusive. Consequently, our study aimed to investigate the microbial community composition in glioma tissues and elucidate its role in glioma development. We parallelly performed microbial profiling, transcriptome sequencing, and metabolomics detection on tumor and adjacent normal brain tissues obtained from 50 glioma patients. We employed immunohistochemistry, multicolor immunofluorescence, and fluorescence in situ hybridization (FISH) staining to observe the presence and location of bacteria. Furthermore, an animal model was employed to validate the impact of key bacteria on glioma development. Six genera were found to be significantly enriched in glioma tissues compared to adjacent normal brain tissues, including Fusobacterium, Longibaculum, Intestinimonas, Pasteurella, Limosilactobacillus, and Arthrobacter. Both bacterial RNA and lipopolysaccharides (LPS) were observed in glioma tissues. Integrated microbiomics, transcriptomics, and metabolomics revealed that genes associated with intratumoral microbes were enriched in multiple synapse-associated pathways and that metabolites associated with intratumoral microbes were (R)-N-methylsalsolinol, N-acetylaspartylglutamic acid, and N-acetyl-l-aspartic acid. Further mediation analysis suggested that the intratumoral microbiome may affect the expression of neuron-related genes through bacteria-associated metabolites. In addition, both in vivo and in vitro models of glioma show that Fusobacterium nucleatum promotes glioma proliferation and upregulates CCL2, CXCL1, and CXCL2 levels. Our findings shed light on the intricate interplay between intratumoral bacteria and glioma.ImportanceOur study adopted a multi-omics approach to unravel the impact of intratumoral microbes on neuron-related gene expression through bacteria-associated metabolites. Importantly, we found bacterial RNA and LPS signals within glioma tissues, which were traditionally considered sterile. We identified key microbiota within glioma tissues, including Fusobacterium nucleatum (Fn). Through in vivo and in vitro experiments, we identified the crucial role of Fn in promoting glioma progression, suggesting that Fn could be a potential diagnostic and therapeutic target for glioma patients. These findings offer valuable insights into the intricate interplay between intratumoral bacteria and glioma, offering novel inspiration to the realm of glioma biology.

Dataset Information

Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma.

Publications

Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma.

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