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Long-range Oncogenic Activation of IgH/c-myc Translocations by the IgH 3’ Regulatory Region

B cell malignancies, such as human Burkitt’s lymphoma (BL), often harbor translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH)1. The nature of elements that activate oncogenes within such translocations has been a longstanding question. Translocations...

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Autores principales: Gostissa, Monica, Yan, Catherine T., Bianco, Julia M., Cogné, Michel, Pinaud, Eric, Alt, Frederick W.
Formato: Texto
Lenguaje:English
Publicado: 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802177/
https://www.ncbi.nlm.nih.gov/pubmed/20010689
http://dx.doi.org/10.1038/nature08633
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author Gostissa, Monica
Yan, Catherine T.
Bianco, Julia M.
Cogné, Michel
Pinaud, Eric
Alt, Frederick W.
author_facet Gostissa, Monica
Yan, Catherine T.
Bianco, Julia M.
Cogné, Michel
Pinaud, Eric
Alt, Frederick W.
author_sort Gostissa, Monica
collection PubMed
description B cell malignancies, such as human Burkitt’s lymphoma (BL), often harbor translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH)1. The nature of elements that activate oncogenes within such translocations has been a longstanding question. Translocations within IgH involve DNA double strand breaks (DSBs) initiated either by the RAG1/2 endonuclease during V(D)J recombination or by activation induced cytidine deaminase (AID) during class switch recombination (CSR)2-4. V(D)J recombination in progenitor B (pro-B) cells assembles IgH variable region exons upstream of μ constant region (Cμ) exons, which are the first of several sets of C(H) exons (“C(H) genes”) within a C(H) locus that spans several hundred kilobases5,6. In mature B cells, CSR deletes Cμ and replaces it with a downstream C(H) gene6. An enhancer (iEμ) between the variable region exons and Cμ promotes V(D)J recombination in developing B cells7. In addition, the IgH 3’ regulatory region (IgH3’RR) lies downstream of the C(H) locus and modulates CSR by long-range transcriptional enhancement of C(H) genes8-10. Transgenic mice bearing iEμ or IgH3’RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating such elements can confer oncogenic c-myc expression11-16. However, in many B cell lymphomas, IgH/c-myc translocations delete iEμ and place c-myc up to 200kb upstream of the IgH3’RR1. We now address the oncogenic role of the IgH3’RR by inactivating it in two distinct mouse models for B cell lymphoma with IgH/c-myc translocations. The IgH3’RR is dispensable for pro-B lymphomas with V(D)J recombination-initiated translocations, but required for peripheral B cell lymphomas with CSR-associated translocations. As the IgH3’RR is not required for CSR-associated IgH breaks or IgH/c-myc translocations in peripheral B cell lymphoma progenitors, we conclude this regulatory region confers oncogenic activity via long-range and developmental stage-specific activation of translocated c-myc genes.
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spelling pubmed-28021772010-06-10 Long-range Oncogenic Activation of IgH/c-myc Translocations by the IgH 3’ Regulatory Region Gostissa, Monica Yan, Catherine T. Bianco, Julia M. Cogné, Michel Pinaud, Eric Alt, Frederick W. Nature Article B cell malignancies, such as human Burkitt’s lymphoma (BL), often harbor translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH)1. The nature of elements that activate oncogenes within such translocations has been a longstanding question. Translocations within IgH involve DNA double strand breaks (DSBs) initiated either by the RAG1/2 endonuclease during V(D)J recombination or by activation induced cytidine deaminase (AID) during class switch recombination (CSR)2-4. V(D)J recombination in progenitor B (pro-B) cells assembles IgH variable region exons upstream of μ constant region (Cμ) exons, which are the first of several sets of C(H) exons (“C(H) genes”) within a C(H) locus that spans several hundred kilobases5,6. In mature B cells, CSR deletes Cμ and replaces it with a downstream C(H) gene6. An enhancer (iEμ) between the variable region exons and Cμ promotes V(D)J recombination in developing B cells7. In addition, the IgH 3’ regulatory region (IgH3’RR) lies downstream of the C(H) locus and modulates CSR by long-range transcriptional enhancement of C(H) genes8-10. Transgenic mice bearing iEμ or IgH3’RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating such elements can confer oncogenic c-myc expression11-16. However, in many B cell lymphomas, IgH/c-myc translocations delete iEμ and place c-myc up to 200kb upstream of the IgH3’RR1. We now address the oncogenic role of the IgH3’RR by inactivating it in two distinct mouse models for B cell lymphoma with IgH/c-myc translocations. The IgH3’RR is dispensable for pro-B lymphomas with V(D)J recombination-initiated translocations, but required for peripheral B cell lymphomas with CSR-associated translocations. As the IgH3’RR is not required for CSR-associated IgH breaks or IgH/c-myc translocations in peripheral B cell lymphoma progenitors, we conclude this regulatory region confers oncogenic activity via long-range and developmental stage-specific activation of translocated c-myc genes. 2009-12-10 /pmc/articles/PMC2802177/ /pubmed/20010689 http://dx.doi.org/10.1038/nature08633 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Gostissa, Monica
Yan, Catherine T.
Bianco, Julia M.
Cogné, Michel
Pinaud, Eric
Alt, Frederick W.
Long-range Oncogenic Activation of IgH/c-myc Translocations by the IgH 3’ Regulatory Region
title Long-range Oncogenic Activation of IgH/c-myc Translocations by the IgH 3’ Regulatory Region
title_full Long-range Oncogenic Activation of IgH/c-myc Translocations by the IgH 3’ Regulatory Region
title_fullStr Long-range Oncogenic Activation of IgH/c-myc Translocations by the IgH 3’ Regulatory Region
title_full_unstemmed Long-range Oncogenic Activation of IgH/c-myc Translocations by the IgH 3’ Regulatory Region
title_short Long-range Oncogenic Activation of IgH/c-myc Translocations by the IgH 3’ Regulatory Region
title_sort long-range oncogenic activation of igh/c-myc translocations by the igh 3’ regulatory region
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802177/
https://www.ncbi.nlm.nih.gov/pubmed/20010689
http://dx.doi.org/10.1038/nature08633
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