title: AID-associated DNA repair pathways regulate malignant transformation in a murine model of BCL6-driven diffuse large B-cell lymphoma.
abstract: Somatic hypermutation and class-switch recombination of the immunoglobulin (Ig) genes occur in germinal center (GC) B cells and are initiated through deamination of cytidine to uracil by activation-induced cytidine deaminase (AID). Resulting uracil-guanine mismatches are processed by uracil DNA glycosylase (UNG)-mediated base-excision repair and MSH2-mediated mismatch repair (MMR) to yield mutations and DNA strand lesions. Although off-target AID activity also contributes to oncogenic point mutations and chromosome translocations associated with GC and post-GC B-cell lymphomas, the role of downstream AID-associated DNA repair pathways in the pathogenesis of lymphoma is unknown. Here, we show that simultaneous deficiency of UNG and MSH2 or MSH2 alone causes genomic instability and a shorter latency to the development of BCL6-driven diffuse large B-cell lymphoma (DLBCL) in a murine model. The additional development of several BCL6-independent malignancies in these mice underscores the critical role of MMR in maintaining general genomic stability. In contrast, absence of UNG alone is highly protective and prevents the development of BCL6-driven DLBCL. We further demonstrate that clonal and nonclonal mutations arise within non-Ig AID target genes in the combined absence of UNG and MSH2 and that DNA strand lesions arise in an UNG-dependent manner but are offset by MSH2. These findings lend insight into a complex interplay whereby potentially deleterious UNG activity and general genomic instability are opposed by the protective influence of MSH2, producing a net protective effect that promotes immune diversification while simultaneously attenuating malignant transformation of GC B cells.
authors.affiliation: Yale Cancer Center, Section of Hematology.
authors.forename: Xiwen
authors.initials: X
authors.lastname: Gu
authors.affiliation: Section of Comparative Medicine, and.
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Booth
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT.
authors.forename: Zongzhi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Yale Cancer Center, Section of Hematology.
authors.forename: Matthew P
authors.identifier: http://orcid.org/0000-0002-9660-3652
authors.initials: MP
authors.lastname: Strout
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D003564:Cytidine Deaminase / Q000378:metabolism*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D018858:Germinal Center; D007124:Immunoenzyme Techniques; D017578:Immunoglobulin Class Switching / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein / Q000502:physiology*; D009154:Mutation; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D032681:Spectral Karyotyping; D014407:Tumor Cells, Cultured; D051981:Uracil-DNA Glycosidase / Q000502:physiology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein