BCL6--regulated by AhR/ARNT and wild-type MEF2B--drives expression of germinal center markers MYBL1 and LMO2.

2.50
Hdl Handle:
http://hdl.handle.net/10033/599254
Title:
BCL6--regulated by AhR/ARNT and wild-type MEF2B--drives expression of germinal center markers MYBL1 and LMO2.
Authors:
Ding, Jie; Dirks, Wilhelm G; Ehrentraut, Stefan; Geffers, Robert ( 0000-0003-4409-016X ) ; MacLeod, Roderick A F; Nagel, Stefan; Pommerenke, Claudia; Romani, Julia; Scherr, Michaela; Vaas, Lea A I; Zaborski, Margarete; Drexler, Hans G; Quentmeier, Hilmar
Abstract:
Genetic heterogeneity is widespread in tumors, but poorly documented in cell lines. According to immunoglobulin hypermutation analysis, the diffuse large B-cell lymphoma cell line U-2932 comprises two subpopulations faithfully representing original tumor subclones. We set out to identify molecular causes underlying subclone-specific expression affecting 221 genes including surface markers and the germinal center oncogenes BCL6 and MYC. Genomic copy number variations explained 58/221 genes differentially expressed in the two U-2932 clones. Subclone-specific expression of the aryl-hydrocarbon receptor (AhR) and the resulting activity of the AhR/ARNT complex underlaid differential regulation of 11 genes including MEF2B. Knock-down and inhibitor experiments confirmed that AhR/ARNT regulates MEF2B, a key transcription factor for BCL6. AhR, MEF2B and BCL6 levels correlated not only in the U-2932 subclones but in the majority of 23 cell lines tested, indicting overexpression of AhR as a novel mechanism behind BCL6 diffuse large B-cell lymphoma. Enforced modulation of BCL6 affected 48/221 signature genes. Although BCL6 is known as a transcriptional repressor, 28 genes were up-regulated, including LMO2 and MYBL1 which, like BCL6, signify germinal center diffuse large B-cell lymphoma. Supporting the notion that BCL6 can induce gene expression, BCL6 and the majority of potential targets were co-regulated in a series of B-cell lines. In conclusion, genomic copy number aberrations, activation of AhR/ARNT, and overexpression of BCL6 are collectively responsible for differential expression of more than 100 genes in subclones of the U-2932 cell line. It is particularly interesting that BCL6 - regulated by AhR/ARNT and wild-type MEF2B - may drive expression of germinal center markers in diffuse large B-cell lymphoma.
Affiliation:
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
Citation:
BCL6--regulated by AhR/ARNT and wild-type MEF2B--drives expression of germinal center markers MYBL1 and LMO2. 2015, 100 (6):801-9 Haematologica
Journal:
Haematologica
Issue Date:
Jun-2015
URI:
http://hdl.handle.net/10033/599254
DOI:
10.3324/haematol.2014.120048
PubMed ID:
25769544
Type:
Article
Language:
en
ISSN:
1592-8721
Appears in Collections:
publications of the research group genomeanalytics (GMAK)

Full metadata record

DC FieldValue Language
dc.contributor.authorDing, Jieen
dc.contributor.authorDirks, Wilhelm Gen
dc.contributor.authorEhrentraut, Stefanen
dc.contributor.authorGeffers, Roberten
dc.contributor.authorMacLeod, Roderick A Fen
dc.contributor.authorNagel, Stefanen
dc.contributor.authorPommerenke, Claudiaen
dc.contributor.authorRomani, Juliaen
dc.contributor.authorScherr, Michaelaen
dc.contributor.authorVaas, Lea A Ien
dc.contributor.authorZaborski, Margareteen
dc.contributor.authorDrexler, Hans Gen
dc.contributor.authorQuentmeier, Hilmaren
dc.date.accessioned2016-02-25T14:59:25Zen
dc.date.available2016-02-25T14:59:25Zen
dc.date.issued2015-06en
dc.identifier.citationBCL6--regulated by AhR/ARNT and wild-type MEF2B--drives expression of germinal center markers MYBL1 and LMO2. 2015, 100 (6):801-9 Haematologicaen
dc.identifier.issn1592-8721en
dc.identifier.pmid25769544en
dc.identifier.doi10.3324/haematol.2014.120048en
dc.identifier.urihttp://hdl.handle.net/10033/599254en
dc.description.abstractGenetic heterogeneity is widespread in tumors, but poorly documented in cell lines. According to immunoglobulin hypermutation analysis, the diffuse large B-cell lymphoma cell line U-2932 comprises two subpopulations faithfully representing original tumor subclones. We set out to identify molecular causes underlying subclone-specific expression affecting 221 genes including surface markers and the germinal center oncogenes BCL6 and MYC. Genomic copy number variations explained 58/221 genes differentially expressed in the two U-2932 clones. Subclone-specific expression of the aryl-hydrocarbon receptor (AhR) and the resulting activity of the AhR/ARNT complex underlaid differential regulation of 11 genes including MEF2B. Knock-down and inhibitor experiments confirmed that AhR/ARNT regulates MEF2B, a key transcription factor for BCL6. AhR, MEF2B and BCL6 levels correlated not only in the U-2932 subclones but in the majority of 23 cell lines tested, indicting overexpression of AhR as a novel mechanism behind BCL6 diffuse large B-cell lymphoma. Enforced modulation of BCL6 affected 48/221 signature genes. Although BCL6 is known as a transcriptional repressor, 28 genes were up-regulated, including LMO2 and MYBL1 which, like BCL6, signify germinal center diffuse large B-cell lymphoma. Supporting the notion that BCL6 can induce gene expression, BCL6 and the majority of potential targets were co-regulated in a series of B-cell lines. In conclusion, genomic copy number aberrations, activation of AhR/ARNT, and overexpression of BCL6 are collectively responsible for differential expression of more than 100 genes in subclones of the U-2932 cell line. It is particularly interesting that BCL6 - regulated by AhR/ARNT and wild-type MEF2B - may drive expression of germinal center markers in diffuse large B-cell lymphoma.en
dc.language.isoenen
dc.subject.meshAdaptor Proteins, Signal Transducingen
dc.subject.meshAryl Hydrocarbon Receptor Nuclear Translocatoren
dc.subject.meshBasic Helix-Loop-Helix Transcription Factorsen
dc.subject.meshBiomarkers, Tumoren
dc.subject.meshCell Line, Tumoren
dc.subject.meshDNA-Binding Proteinsen
dc.subject.meshGene Expression Regulation, Neoplasticen
dc.subject.meshGerminal Centeren
dc.subject.meshHumansen
dc.subject.meshLIM Domain Proteinsen
dc.subject.meshLymphoma, Large B-Cell, Diffuseen
dc.subject.meshMEF2 Transcription Factorsen
dc.subject.meshProto-Oncogene Proteinsen
dc.subject.meshReceptors, Aryl Hydrocarbonen
dc.subject.meshTrans-Activatorsen
dc.titleBCL6--regulated by AhR/ARNT and wild-type MEF2B--drives expression of germinal center markers MYBL1 and LMO2.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.en
dc.identifier.journalHaematologicaen

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