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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...

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Autores principales: 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.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2008
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.
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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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