Title |
Combined deletion of Xrcc4 and Trp53 in mouse germinal center B cells leads to novel B cell lymphomas with clonal heterogeneity
|
---|---|
Published in |
Journal of Hematology & Oncology, January 2016
|
DOI | 10.1186/s13045-015-0230-5 |
Pubmed ID | |
Authors |
Zhangguo Chen, Mihret T. Elos, Sawanee S. Viboolsittiseri, Katherine Gowan, Sonia M. Leach, Michael Rice, Maxwell D. Eder, Kenneth Jones, Jing H. Wang |
Abstract |
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. 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. 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. 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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 17 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 3 | 18% |
Student > Ph. D. Student | 3 | 18% |
Other | 1 | 6% |
Student > Doctoral Student | 1 | 6% |
Student > Bachelor | 1 | 6% |
Other | 5 | 29% |
Unknown | 3 | 18% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 7 | 41% |
Agricultural and Biological Sciences | 3 | 18% |
Unspecified | 1 | 6% |
Computer Science | 1 | 6% |
Immunology and Microbiology | 1 | 6% |
Other | 0 | 0% |
Unknown | 4 | 24% |