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- Title
Combined deletion of Xrcc4 and Trp53 in mouse germinal center B cells leads to novel B cell lymphomas with clonal heterogeneity.
- Authors
Zhangguo Chen; Elos, Mihret T.; Viboolsittiseri, Sawanee S.; Gowan, Katherine; Leach, Sonia M.; Rice, Michael; Eder, Maxwell D.; Jones, Kenneth; Wang, Jing H.
- Abstract
Background: Activated B lymphocytes harbor programmed DNA double-strand breaks (DSBs) initiated by activation-induced deaminase (AID) and repaired by non-homologous end-joining (NHEJ). While it has been proposed that these DSBs during secondary antibody gene diversification are the primary source of chromosomal translocations in germinal center (GC)-derived B cell lymphomas, this point has not been directly addressed due to the lack of proper mouse models. Methods: In the current study, we establish a unique mouse model by specifically deleting a NHEJ gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in GC B cells, which results in the spontaneous development of B cell lymphomas that possess features of GC B cells. Results: We show that these NHEJ deficient lymphomas harbor translocations frequently targeting immunoglobulin (Ig) loci. Furthermore, we found that Ig translocations were associated with distinct mechanisms, probably caused by AID- or RAG-induced DSBs. Intriguingly, the AID-associated Ig loci translocations target either c-myc or Pvt-1 locus whereas the partners of RAG-associated Ig translocations scattered randomly in the genome. Lastly, these NHEJ deficient lymphomas harbor complicated genomes including segmental translocations and exhibit a high level of ongoing DNA damage and clonal heterogeneity. Conclusions: We propose that combined NHEJ and p53 defects may serve as an underlying mechanism for a high level of genomic complexity and clonal heterogeneity in cancers.
- Subjects
B cells; LYMPHOMAS; DOUBLE-strand polymers; CHROMOSOMAL translocation; DEAMINASES; GERMINAL centers; CELL cycle
- Publication
Journal of Hematology & Oncology, 2016, Vol 9, p1
- ISSN
1756-8722
- Publication type
Article
- DOI
10.1186/s13045-015-0230-5