In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 16, No. 12 ( 2020-12-23), p. e1008960-
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.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1008960
DOI:
10.1371/journal.pgen.1008960.g001
DOI:
10.1371/journal.pgen.1008960.g002
DOI:
10.1371/journal.pgen.1008960.g003
DOI:
10.1371/journal.pgen.1008960.g004
DOI:
10.1371/journal.pgen.1008960.g005
DOI:
10.1371/journal.pgen.1008960.g006
DOI:
10.1371/journal.pgen.1008960.s001
DOI:
10.1371/journal.pgen.1008960.s002
DOI:
10.1371/journal.pgen.1008960.s003
DOI:
10.1371/journal.pgen.1008960.s004
DOI:
10.1371/journal.pgen.1008960.s005
DOI:
10.1371/journal.pgen.1008960.s006
DOI:
10.1371/journal.pgen.1008960.s007
DOI:
10.1371/journal.pgen.1008960.s008
DOI:
10.1371/journal.pgen.1008960.s009
DOI:
10.1371/journal.pgen.1008960.s010
DOI:
10.1371/journal.pgen.1008960.s011
DOI:
10.1371/journal.pgen.1008960.s012
DOI:
10.1371/journal.pgen.1008960.s013
DOI:
10.1371/journal.pgen.1008960.r001
DOI:
10.1371/journal.pgen.1008960.r002
DOI:
10.1371/journal.pgen.1008960.r003
DOI:
10.1371/journal.pgen.1008960.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2020
detail.hit.zdb_id:
2186725-2
