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SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity
Interferon regulatory factor 4 (IRF4) is central to the transcriptional network of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), an aggressive lymphoma subgroup defined by gene expression profiling. Since cofactor association modifies transcriptional regulatory input by IRF4, we a...
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| Published in: | Nucleic acids research 2014-07, Vol.42 (12), p.7591-7610 |
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| container_title | Nucleic acids research |
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| creator | Care, Matthew A Cocco, Mario Laye, Jon P Barnes, Nicholas Huang, Yuanxue Wang, Ming Barrans, Sharon Du, Ming Jack, Andrew Westhead, David R Doody, Gina M Tooze, Reuben M |
| description | Interferon regulatory factor 4 (IRF4) is central to the transcriptional network of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), an aggressive lymphoma subgroup defined by gene expression profiling. Since cofactor association modifies transcriptional regulatory input by IRF4, we assessed genome occupancy by IRF4 and endogenous cofactors in ABC-DLBCL cell lines. IRF4 partners with SPIB, PU.1 and BATF genome-wide, but SPIB provides the dominant IRF4 partner in this context. Upon SPIB knockdown IRF4 occupancy is depleted and neither PU.1 nor BATF acutely compensates. Integration with ENCODE data from lymphoblastoid cell line GM12878, demonstrates that IRF4 adopts either SPIB- or BATF-centric genome-wide distributions in related states of post-germinal centre B-cell transformation. In primary DLBCL high-SPIB and low-BATF or the reciprocal low-SPIB and high-BATF mRNA expression links to differential gene expression profiles across nine data sets, identifying distinct associations with SPIB occupancy, signatures of B-cell differentiation stage and potential pathogenetic mechanisms. In a population-based patient cohort, SPIBhigh/BATFlow-ABC-DLBCL is enriched for mutation of MYD88, and SPIBhigh/BATFlow-ABC-DLBCL with MYD88-L265P mutation identifies a small subgroup of patients among this otherwise aggressive disease subgroup with distinct favourable outcome. We conclude that differential expression of IRF4 cofactors SPIB and BATF identifies biologically and clinically significant heterogeneity among ABC-DLBCL. |
| doi_str_mv | 10.1093/nar/gku451 |
| format | article |
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Since cofactor association modifies transcriptional regulatory input by IRF4, we assessed genome occupancy by IRF4 and endogenous cofactors in ABC-DLBCL cell lines. IRF4 partners with SPIB, PU.1 and BATF genome-wide, but SPIB provides the dominant IRF4 partner in this context. Upon SPIB knockdown IRF4 occupancy is depleted and neither PU.1 nor BATF acutely compensates. Integration with ENCODE data from lymphoblastoid cell line GM12878, demonstrates that IRF4 adopts either SPIB- or BATF-centric genome-wide distributions in related states of post-germinal centre B-cell transformation. In primary DLBCL high-SPIB and low-BATF or the reciprocal low-SPIB and high-BATF mRNA expression links to differential gene expression profiles across nine data sets, identifying distinct associations with SPIB occupancy, signatures of B-cell differentiation stage and potential pathogenetic mechanisms. In a population-based patient cohort, SPIBhigh/BATFlow-ABC-DLBCL is enriched for mutation of MYD88, and SPIBhigh/BATFlow-ABC-DLBCL with MYD88-L265P mutation identifies a small subgroup of patients among this otherwise aggressive disease subgroup with distinct favourable outcome. We conclude that differential expression of IRF4 cofactors SPIB and BATF identifies biologically and clinically significant heterogeneity among ABC-DLBCL.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gku451</identifier><identifier>PMID: 24875472</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>B-Lymphocytes - cytology ; Basic-Leucine Zipper Transcription Factors - metabolism ; Binding Sites ; Cell Differentiation ; Cell Line, Tumor ; DNA-Binding Proteins - metabolism ; Gene Expression Regulation, Neoplastic ; Gene regulation, Chromatin and Epigenetics ; Humans ; Interferon Regulatory Factors - metabolism ; Lymphoma, Large B-Cell, Diffuse - genetics ; Lymphoma, Large B-Cell, Diffuse - metabolism ; Lymphoma, Large B-Cell, Diffuse - mortality ; Mutation ; Myeloid Differentiation Factor 88 - genetics ; Nucleotide Motifs ; Proto-Oncogene Proteins - metabolism ; Trans-Activators - metabolism ; Transcription Factors - metabolism</subject><ispartof>Nucleic acids research, 2014-07, Vol.42 (12), p.7591-7610</ispartof><rights>The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><rights>The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-5e813cc66f922a3543b847bd418b24816643192ed8893eba360d1b53ddbd9ea23</citedby><cites>FETCH-LOGICAL-c477t-5e813cc66f922a3543b847bd418b24816643192ed8893eba360d1b53ddbd9ea23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081075/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081075/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24875472$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Care, Matthew A</creatorcontrib><creatorcontrib>Cocco, Mario</creatorcontrib><creatorcontrib>Laye, Jon P</creatorcontrib><creatorcontrib>Barnes, Nicholas</creatorcontrib><creatorcontrib>Huang, Yuanxue</creatorcontrib><creatorcontrib>Wang, Ming</creatorcontrib><creatorcontrib>Barrans, Sharon</creatorcontrib><creatorcontrib>Du, Ming</creatorcontrib><creatorcontrib>Jack, Andrew</creatorcontrib><creatorcontrib>Westhead, David R</creatorcontrib><creatorcontrib>Doody, Gina M</creatorcontrib><creatorcontrib>Tooze, Reuben M</creatorcontrib><title>SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Interferon regulatory factor 4 (IRF4) is central to the transcriptional network of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), an aggressive lymphoma subgroup defined by gene expression profiling. Since cofactor association modifies transcriptional regulatory input by IRF4, we assessed genome occupancy by IRF4 and endogenous cofactors in ABC-DLBCL cell lines. IRF4 partners with SPIB, PU.1 and BATF genome-wide, but SPIB provides the dominant IRF4 partner in this context. Upon SPIB knockdown IRF4 occupancy is depleted and neither PU.1 nor BATF acutely compensates. Integration with ENCODE data from lymphoblastoid cell line GM12878, demonstrates that IRF4 adopts either SPIB- or BATF-centric genome-wide distributions in related states of post-germinal centre B-cell transformation. In primary DLBCL high-SPIB and low-BATF or the reciprocal low-SPIB and high-BATF mRNA expression links to differential gene expression profiles across nine data sets, identifying distinct associations with SPIB occupancy, signatures of B-cell differentiation stage and potential pathogenetic mechanisms. In a population-based patient cohort, SPIBhigh/BATFlow-ABC-DLBCL is enriched for mutation of MYD88, and SPIBhigh/BATFlow-ABC-DLBCL with MYD88-L265P mutation identifies a small subgroup of patients among this otherwise aggressive disease subgroup with distinct favourable outcome. We conclude that differential expression of IRF4 cofactors SPIB and BATF identifies biologically and clinically significant heterogeneity among ABC-DLBCL.</description><subject>B-Lymphocytes - cytology</subject><subject>Basic-Leucine Zipper Transcription Factors - metabolism</subject><subject>Binding Sites</subject><subject>Cell Differentiation</subject><subject>Cell Line, Tumor</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene regulation, Chromatin and Epigenetics</subject><subject>Humans</subject><subject>Interferon Regulatory Factors - metabolism</subject><subject>Lymphoma, Large B-Cell, Diffuse - genetics</subject><subject>Lymphoma, Large B-Cell, Diffuse - metabolism</subject><subject>Lymphoma, Large B-Cell, Diffuse - mortality</subject><subject>Mutation</subject><subject>Myeloid Differentiation Factor 88 - genetics</subject><subject>Nucleotide Motifs</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Trans-Activators - metabolism</subject><subject>Transcription Factors - metabolism</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNqFkU2LFDEQhoMo7rh68QdIjrLQbj670xdhZ3F0YEHR9RzSSfVM3O6kTboX5uRfN8Osi548VUE9vNTLg9BrSt5R0vLLYNLl7m4Rkj5BK8prVom2Zk_RinAiK0qEOkMvcv5BCBVUiufojAnVSNGwFfr17ct2jU1weH11u8FTivfeATbDDCmYGbCDso0-mDBnHHu8_boROFq7TCbYA_YBO9_3SwY8mLQDvK4sDAMeDuO0j6PBgw934PAcC5fBFG5_TIw7CODnw0v0rDdDhlcP8xx933y4vf5U3Xz-uL2-uqmsaJq5kqAot7au-5Yxw6XgnRJN5wRVXSlD61pw2jJwSrUcOsNr4mgnuXOda8Ewfo7en3KnpRvBWQhzMoOekh9NOuhovP73Evxe7-K9FkRR0sgS8PYhIMWfC-RZjz4fq5oAccmaKqLqVtRFyH_R8j5TQqpj6sUJtSnmnKB__IgSfZSri1x9klvgN393eET_2OS_ATDkojA</recordid><startdate>20140708</startdate><enddate>20140708</enddate><creator>Care, Matthew A</creator><creator>Cocco, Mario</creator><creator>Laye, Jon P</creator><creator>Barnes, Nicholas</creator><creator>Huang, Yuanxue</creator><creator>Wang, Ming</creator><creator>Barrans, Sharon</creator><creator>Du, Ming</creator><creator>Jack, Andrew</creator><creator>Westhead, David R</creator><creator>Doody, Gina M</creator><creator>Tooze, Reuben M</creator><general>Oxford University Press</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>7X8</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20140708</creationdate><title>SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity</title><author>Care, Matthew A ; Cocco, Mario ; Laye, Jon P ; Barnes, Nicholas ; Huang, Yuanxue ; Wang, Ming ; Barrans, Sharon ; Du, Ming ; Jack, Andrew ; Westhead, David R ; Doody, Gina M ; Tooze, Reuben M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-5e813cc66f922a3543b847bd418b24816643192ed8893eba360d1b53ddbd9ea23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>B-Lymphocytes - cytology</topic><topic>Basic-Leucine Zipper Transcription Factors - metabolism</topic><topic>Binding Sites</topic><topic>Cell Differentiation</topic><topic>Cell Line, Tumor</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene regulation, Chromatin and Epigenetics</topic><topic>Humans</topic><topic>Interferon Regulatory Factors - metabolism</topic><topic>Lymphoma, Large B-Cell, Diffuse - genetics</topic><topic>Lymphoma, Large B-Cell, Diffuse - metabolism</topic><topic>Lymphoma, Large B-Cell, Diffuse - mortality</topic><topic>Mutation</topic><topic>Myeloid Differentiation Factor 88 - genetics</topic><topic>Nucleotide Motifs</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Trans-Activators - metabolism</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Care, Matthew A</creatorcontrib><creatorcontrib>Cocco, Mario</creatorcontrib><creatorcontrib>Laye, Jon P</creatorcontrib><creatorcontrib>Barnes, Nicholas</creatorcontrib><creatorcontrib>Huang, Yuanxue</creatorcontrib><creatorcontrib>Wang, Ming</creatorcontrib><creatorcontrib>Barrans, Sharon</creatorcontrib><creatorcontrib>Du, Ming</creatorcontrib><creatorcontrib>Jack, Andrew</creatorcontrib><creatorcontrib>Westhead, David R</creatorcontrib><creatorcontrib>Doody, Gina M</creatorcontrib><creatorcontrib>Tooze, Reuben M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Care, Matthew A</au><au>Cocco, Mario</au><au>Laye, Jon P</au><au>Barnes, Nicholas</au><au>Huang, Yuanxue</au><au>Wang, Ming</au><au>Barrans, Sharon</au><au>Du, Ming</au><au>Jack, Andrew</au><au>Westhead, David R</au><au>Doody, Gina M</au><au>Tooze, Reuben M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2014-07-08</date><risdate>2014</risdate><volume>42</volume><issue>12</issue><spage>7591</spage><epage>7610</epage><pages>7591-7610</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>The authors wish it to be known that, in their opinion, the first two authors should be considered as Joint First Authors.</notes><abstract>Interferon regulatory factor 4 (IRF4) is central to the transcriptional network of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), an aggressive lymphoma subgroup defined by gene expression profiling. Since cofactor association modifies transcriptional regulatory input by IRF4, we assessed genome occupancy by IRF4 and endogenous cofactors in ABC-DLBCL cell lines. IRF4 partners with SPIB, PU.1 and BATF genome-wide, but SPIB provides the dominant IRF4 partner in this context. Upon SPIB knockdown IRF4 occupancy is depleted and neither PU.1 nor BATF acutely compensates. Integration with ENCODE data from lymphoblastoid cell line GM12878, demonstrates that IRF4 adopts either SPIB- or BATF-centric genome-wide distributions in related states of post-germinal centre B-cell transformation. In primary DLBCL high-SPIB and low-BATF or the reciprocal low-SPIB and high-BATF mRNA expression links to differential gene expression profiles across nine data sets, identifying distinct associations with SPIB occupancy, signatures of B-cell differentiation stage and potential pathogenetic mechanisms. In a population-based patient cohort, SPIBhigh/BATFlow-ABC-DLBCL is enriched for mutation of MYD88, and SPIBhigh/BATFlow-ABC-DLBCL with MYD88-L265P mutation identifies a small subgroup of patients among this otherwise aggressive disease subgroup with distinct favourable outcome. We conclude that differential expression of IRF4 cofactors SPIB and BATF identifies biologically and clinically significant heterogeneity among ABC-DLBCL.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>24875472</pmid><doi>10.1093/nar/gku451</doi><tpages>20</tpages><oa>free_for_read</oa></addata></record> |
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| source | OUP_牛津大学出版社现刊; PubMed Central (Training) |
| subjects | B-Lymphocytes - cytology Basic-Leucine Zipper Transcription Factors - metabolism Binding Sites Cell Differentiation Cell Line, Tumor DNA-Binding Proteins - metabolism Gene Expression Regulation, Neoplastic Gene regulation, Chromatin and Epigenetics Humans Interferon Regulatory Factors - metabolism Lymphoma, Large B-Cell, Diffuse - genetics Lymphoma, Large B-Cell, Diffuse - metabolism Lymphoma, Large B-Cell, Diffuse - mortality Mutation Myeloid Differentiation Factor 88 - genetics Nucleotide Motifs Proto-Oncogene Proteins - metabolism Trans-Activators - metabolism Transcription Factors - metabolism |
| title | SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity |
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