Negative Autoregulation of BCL-6 Is Bypassed by Genetic Alterations in Diffuse Large B Cell Lymphomas
Thirty to forty percent of diffuse large B cell lymphomas (DLBCL) carry BCL-6 translocations that disrupt its 5′ regulatory region. This same region is also subject to somatic hypermutations, although only a small fraction of these mutations have a detectable effect on transcription. Here, we show t...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2002-11, Vol.99 (23), p.15018-15023 |
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| creator | Wang, Xing Li, Zhiping Naganuma, Akira Ye, B. Hilda |
| description | Thirty to forty percent of diffuse large B cell lymphomas (DLBCL) carry BCL-6 translocations that disrupt its 5′ regulatory region. This same region is also subject to somatic hypermutations, although only a small fraction of these mutations have a detectable effect on transcription. Here, we show that transcription of the BCL-6 gene is negatively self-regulated in multiple cell types. This mechanism operates by means of the interaction of two BCL-6-binding sites within exon 1 of the gene and the BCL-6 protein itself, which is a potent transcription repressor. Because the DLBCL-associated "activating mutations" specifically target these exon 1 binding sites, and because the entire exon 1 is usually removed in the BCL-6-translocated tumors, this autoregulation is bypassed in 30-40% of all DLBCL cases. Our results not only demonstrate an important mechanism governing the expression of BCL-6, but also explain how BCL-6 is deregulated in a large number of DLBCL patients, providing a better understanding of BCL-6-related lymphomagenesis. |
| doi_str_mv | 10.1073/pnas.232581199 |
| format | Article |
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Hilda</creator><creatorcontrib>Wang, Xing ; Li, Zhiping ; Naganuma, Akira ; Ye, B. Hilda</creatorcontrib><description>Thirty to forty percent of diffuse large B cell lymphomas (DLBCL) carry BCL-6 translocations that disrupt its 5′ regulatory region. This same region is also subject to somatic hypermutations, although only a small fraction of these mutations have a detectable effect on transcription. Here, we show that transcription of the BCL-6 gene is negatively self-regulated in multiple cell types. This mechanism operates by means of the interaction of two BCL-6-binding sites within exon 1 of the gene and the BCL-6 protein itself, which is a potent transcription repressor. Because the DLBCL-associated "activating mutations" specifically target these exon 1 binding sites, and because the entire exon 1 is usually removed in the BCL-6-translocated tumors, this autoregulation is bypassed in 30-40% of all DLBCL cases. Our results not only demonstrate an important mechanism governing the expression of BCL-6, but also explain how BCL-6 is deregulated in a large number of DLBCL patients, providing a better understanding of BCL-6-related lymphomagenesis.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.232581199</identifier><identifier>PMID: 12407182</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>3T3 Cells ; Alleles ; Animals ; Autoregulation ; B cell lymphoma ; B lymphocytes ; Base Sequence ; Biological Sciences ; Cell lines ; Cells ; Chromatin - genetics ; Chromatin - immunology ; DNA Primers ; DNA-Binding Proteins - deficiency ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - physiology ; Exons ; Gels ; Gene Expression Regulation, Neoplastic ; Genes, Reporter ; Genetic mutation ; Genetics ; Homeostasis ; Humans ; Lymphoma ; Lymphoma, B-Cell - genetics ; Lymphoma, B-Cell - immunology ; Messenger RNA ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Proto-Oncogene Proteins - deficiency ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - physiology ; Proto-Oncogene Proteins c-bcl-6 ; Repression ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; Transcription Factors - deficiency ; Transcription Factors - genetics ; Transcription Factors - physiology ; Transfection ; Translocation, Genetic</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2002-11, Vol.99 (23), p.15018-15023</ispartof><rights>Copyright 1993-2002 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Nov 12, 2002</rights><rights>Copyright © 2002, The National Academy of Sciences 2002</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c521t-4fc3cfc43843d183800096e109a01a15eeb2bcfc07cbf0165aba87276483ebfa3</citedby><cites>FETCH-LOGICAL-c521t-4fc3cfc43843d183800096e109a01a15eeb2bcfc07cbf0165aba87276483ebfa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/99/23.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3073710$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3073710$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12407182$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Xing</creatorcontrib><creatorcontrib>Li, Zhiping</creatorcontrib><creatorcontrib>Naganuma, Akira</creatorcontrib><creatorcontrib>Ye, B. Hilda</creatorcontrib><title>Negative Autoregulation of BCL-6 Is Bypassed by Genetic Alterations in Diffuse Large B Cell Lymphomas</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Thirty to forty percent of diffuse large B cell lymphomas (DLBCL) carry BCL-6 translocations that disrupt its 5′ regulatory region. This same region is also subject to somatic hypermutations, although only a small fraction of these mutations have a detectable effect on transcription. Here, we show that transcription of the BCL-6 gene is negatively self-regulated in multiple cell types. This mechanism operates by means of the interaction of two BCL-6-binding sites within exon 1 of the gene and the BCL-6 protein itself, which is a potent transcription repressor. Because the DLBCL-associated "activating mutations" specifically target these exon 1 binding sites, and because the entire exon 1 is usually removed in the BCL-6-translocated tumors, this autoregulation is bypassed in 30-40% of all DLBCL cases. Our results not only demonstrate an important mechanism governing the expression of BCL-6, but also explain how BCL-6 is deregulated in a large number of DLBCL patients, providing a better understanding of BCL-6-related lymphomagenesis.</description><subject>3T3 Cells</subject><subject>Alleles</subject><subject>Animals</subject><subject>Autoregulation</subject><subject>B cell lymphoma</subject><subject>B lymphocytes</subject><subject>Base Sequence</subject><subject>Biological Sciences</subject><subject>Cell lines</subject><subject>Cells</subject><subject>Chromatin - genetics</subject><subject>Chromatin - immunology</subject><subject>DNA Primers</subject><subject>DNA-Binding Proteins - deficiency</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - physiology</subject><subject>Exons</subject><subject>Gels</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes, Reporter</subject><subject>Genetic mutation</subject><subject>Genetics</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Lymphoma</subject><subject>Lymphoma, B-Cell - genetics</subject><subject>Lymphoma, B-Cell - immunology</subject><subject>Messenger RNA</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Molecular Sequence Data</subject><subject>Proto-Oncogene Proteins - deficiency</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - physiology</subject><subject>Proto-Oncogene Proteins c-bcl-6</subject><subject>Repression</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>Transcription Factors - deficiency</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - physiology</subject><subject>Transfection</subject><subject>Translocation, Genetic</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkkuP0zAUhS0EYkphywqBxQKxSfG1k9hZsGg7MIwUwQbWlpNed1IlccdORvTfj0NLeSzAG8u637mvY0KeA1sAk-LdvjdhwQXPFEBRPCAzYAUkeVqwh2TGGJeJSnl6QZ6EsGOMFZlij8kF8JRJUHxG8DNuzdDcIV2Og_O4Hdv4dD11lq7WZZLT60BXh70JATe0OtAr7HFoarpsB_Q_0ECbnl421o4BaWn8FumKrrFtaXno9jeuM-EpeWRNG_DZ6Z6Tbx8_fF1_SsovV9frZZnUGYchSW0talunQqViA0qoqeMc40iGgYEMseJVBJisK8sgz0xllOQyT5XAyhoxJ--Pefdj1eGmxn7wptV733TGH7Qzjf4z0jc3euvuNAiZCRn1b056725HDIPumlDHUUyPbgxa8lwW8fwXBJUDL7Ip4-u_wJ0bfR-XoDmDlEPGJmhxhGrvQvBozx0D05PNerJZn22Ogpe_z_kLP_kagVcnYBL-DBdFzKFjybjbOXn7b0LbsY0efx8i-uKI7kL8ImdWxMYkMHEPf6fE7w</recordid><startdate>20021112</startdate><enddate>20021112</enddate><creator>Wang, Xing</creator><creator>Li, Zhiping</creator><creator>Naganuma, Akira</creator><creator>Ye, B. Hilda</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20021112</creationdate><title>Negative Autoregulation of BCL-6 Is Bypassed by Genetic Alterations in Diffuse Large B Cell Lymphomas</title><author>Wang, Xing ; Li, Zhiping ; Naganuma, Akira ; Ye, B. Hilda</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c521t-4fc3cfc43843d183800096e109a01a15eeb2bcfc07cbf0165aba87276483ebfa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>3T3 Cells</topic><topic>Alleles</topic><topic>Animals</topic><topic>Autoregulation</topic><topic>B cell lymphoma</topic><topic>B lymphocytes</topic><topic>Base Sequence</topic><topic>Biological Sciences</topic><topic>Cell lines</topic><topic>Cells</topic><topic>Chromatin - genetics</topic><topic>Chromatin - immunology</topic><topic>DNA Primers</topic><topic>DNA-Binding Proteins - deficiency</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - physiology</topic><topic>Exons</topic><topic>Gels</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genes, Reporter</topic><topic>Genetic mutation</topic><topic>Genetics</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Lymphoma</topic><topic>Lymphoma, B-Cell - genetics</topic><topic>Lymphoma, B-Cell - immunology</topic><topic>Messenger RNA</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Molecular Sequence Data</topic><topic>Proto-Oncogene Proteins - deficiency</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins - physiology</topic><topic>Proto-Oncogene Proteins c-bcl-6</topic><topic>Repression</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - genetics</topic><topic>Transcription Factors - deficiency</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - physiology</topic><topic>Transfection</topic><topic>Translocation, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Xing</creatorcontrib><creatorcontrib>Li, Zhiping</creatorcontrib><creatorcontrib>Naganuma, Akira</creatorcontrib><creatorcontrib>Ye, B. 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Hilda</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Negative Autoregulation of BCL-6 Is Bypassed by Genetic Alterations in Diffuse Large B Cell Lymphomas</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2002-11-12</date><risdate>2002</risdate><volume>99</volume><issue>23</issue><spage>15018</spage><epage>15023</epage><pages>15018-15023</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Thirty to forty percent of diffuse large B cell lymphomas (DLBCL) carry BCL-6 translocations that disrupt its 5′ regulatory region. This same region is also subject to somatic hypermutations, although only a small fraction of these mutations have a detectable effect on transcription. Here, we show that transcription of the BCL-6 gene is negatively self-regulated in multiple cell types. This mechanism operates by means of the interaction of two BCL-6-binding sites within exon 1 of the gene and the BCL-6 protein itself, which is a potent transcription repressor. Because the DLBCL-associated "activating mutations" specifically target these exon 1 binding sites, and because the entire exon 1 is usually removed in the BCL-6-translocated tumors, this autoregulation is bypassed in 30-40% of all DLBCL cases. Our results not only demonstrate an important mechanism governing the expression of BCL-6, but also explain how BCL-6 is deregulated in a large number of DLBCL patients, providing a better understanding of BCL-6-related lymphomagenesis.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>12407182</pmid><doi>10.1073/pnas.232581199</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 3T3 Cells Alleles Animals Autoregulation B cell lymphoma B lymphocytes Base Sequence Biological Sciences Cell lines Cells Chromatin - genetics Chromatin - immunology DNA Primers DNA-Binding Proteins - deficiency DNA-Binding Proteins - genetics DNA-Binding Proteins - physiology Exons Gels Gene Expression Regulation, Neoplastic Genes, Reporter Genetic mutation Genetics Homeostasis Humans Lymphoma Lymphoma, B-Cell - genetics Lymphoma, B-Cell - immunology Messenger RNA Mice Mice, Knockout Molecular Sequence Data Proto-Oncogene Proteins - deficiency Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - physiology Proto-Oncogene Proteins c-bcl-6 Repression Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics Transcription Factors - deficiency Transcription Factors - genetics Transcription Factors - physiology Transfection Translocation, Genetic |
| title | Negative Autoregulation of BCL-6 Is Bypassed by Genetic Alterations in Diffuse Large B Cell Lymphomas |
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