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Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching
Nonhomologous end-joining (NHEJ) repairs DNA double-strand breaks (DSBs) during V(D)J recombination in developing lymphocytes and during immunoglobulin (Ig) heavy chain (IgH) class switch recombination (CSR) in peripheral B lymphocytes. We now show that CD21-cre–mediated deletion of the Xrcc4 NHEJ g...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605230/ https://www.ncbi.nlm.nih.gov/pubmed/19064702 http://dx.doi.org/10.1084/jem.20082271 |
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author | Wang, Jing H. Alt, Frederick W. Gostissa, Monica Datta, Abhishek Murphy, Michael Alimzhanov, Marat B. Coakley, Kristen M. Rajewsky, Klaus Manis, John P. Yan, Catherine T. |
author_facet | Wang, Jing H. Alt, Frederick W. Gostissa, Monica Datta, Abhishek Murphy, Michael Alimzhanov, Marat B. Coakley, Kristen M. Rajewsky, Klaus Manis, John P. Yan, Catherine T. |
author_sort | Wang, Jing H. |
collection | PubMed |
description | Nonhomologous end-joining (NHEJ) repairs DNA double-strand breaks (DSBs) during V(D)J recombination in developing lymphocytes and during immunoglobulin (Ig) heavy chain (IgH) class switch recombination (CSR) in peripheral B lymphocytes. We now show that CD21-cre–mediated deletion of the Xrcc4 NHEJ gene in p53-deficient peripheral B cells leads to recurrent surface Ig-negative B lymphomas (“CXP lymphomas”). Remarkably, CXP lymphomas arise from peripheral B cells that had attempted both receptor editing (secondary V[D]J recombination of Igκ and Igλ light chain genes) and IgH CSR subsequent to Xrcc4 deletion. Correspondingly, CXP tumors frequently harbored a CSR-based reciprocal chromosomal translocation that fused IgH to c-myc, as well as large chromosomal deletions or translocations involving Igκ or Igλ, with the latter fusing Igλ to oncogenes or to IgH. Our findings reveal peripheral B cells that have undergone both editing and CSR and show them to be common progenitors of CXP tumors. Our studies also reveal developmental stage-specific mechanisms of c-myc activation via IgH locus translocations. Thus, Xrcc4/p53-deficient pro–B lymphomas routinely activate c-myc by gene amplification, whereas Xrcc4/p53-deficient peripheral B cell lymphomas routinely ectopically activate a single c-myc copy. |
format | Text |
id | pubmed-2605230 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-26052302009-06-22 Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching Wang, Jing H. Alt, Frederick W. Gostissa, Monica Datta, Abhishek Murphy, Michael Alimzhanov, Marat B. Coakley, Kristen M. Rajewsky, Klaus Manis, John P. Yan, Catherine T. J Exp Med Articles Nonhomologous end-joining (NHEJ) repairs DNA double-strand breaks (DSBs) during V(D)J recombination in developing lymphocytes and during immunoglobulin (Ig) heavy chain (IgH) class switch recombination (CSR) in peripheral B lymphocytes. We now show that CD21-cre–mediated deletion of the Xrcc4 NHEJ gene in p53-deficient peripheral B cells leads to recurrent surface Ig-negative B lymphomas (“CXP lymphomas”). Remarkably, CXP lymphomas arise from peripheral B cells that had attempted both receptor editing (secondary V[D]J recombination of Igκ and Igλ light chain genes) and IgH CSR subsequent to Xrcc4 deletion. Correspondingly, CXP tumors frequently harbored a CSR-based reciprocal chromosomal translocation that fused IgH to c-myc, as well as large chromosomal deletions or translocations involving Igκ or Igλ, with the latter fusing Igλ to oncogenes or to IgH. Our findings reveal peripheral B cells that have undergone both editing and CSR and show them to be common progenitors of CXP tumors. Our studies also reveal developmental stage-specific mechanisms of c-myc activation via IgH locus translocations. Thus, Xrcc4/p53-deficient pro–B lymphomas routinely activate c-myc by gene amplification, whereas Xrcc4/p53-deficient peripheral B cell lymphomas routinely ectopically activate a single c-myc copy. The Rockefeller University Press 2008-12-22 /pmc/articles/PMC2605230/ /pubmed/19064702 http://dx.doi.org/10.1084/jem.20082271 Text en © 2008 Wang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Articles Wang, Jing H. Alt, Frederick W. Gostissa, Monica Datta, Abhishek Murphy, Michael Alimzhanov, Marat B. Coakley, Kristen M. Rajewsky, Klaus Manis, John P. Yan, Catherine T. Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching |
title | Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching |
title_full | Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching |
title_fullStr | Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching |
title_full_unstemmed | Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching |
title_short | Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching |
title_sort | oncogenic transformation in the absence of xrcc4 targets peripheral b cells that have undergone editing and switching |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605230/ https://www.ncbi.nlm.nih.gov/pubmed/19064702 http://dx.doi.org/10.1084/jem.20082271 |
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