Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
PLoS genetics - 16(2020), 12 vom: 24. Dez., Seite e1008960 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Delgado, Pilar [VerfasserIn] |
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| Links: |
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| Themen: |
AICDA (activation-induced cytidine deaminase) |
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| Anmerkungen: |
Date Completed 21.01.2021 Date Revised 30.03.2024 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.1371/journal.pgen.1008960 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM319265153 |
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| 520 | |a 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 | ||
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| 700 | 1 | |a Marina-Zárate, Ester |e verfasserin |4 aut | |
| 700 | 1 | |a Sernandez, Isora V |e verfasserin |4 aut | |
| 700 | 1 | |a Mur, Sonia M |e verfasserin |4 aut | |
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| 700 | 1 | |a Belver, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a de Yébenes, Virginia G |e verfasserin |4 aut | |
| 700 | 1 | |a Ramiro, Almudena R |e verfasserin |4 aut | |
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