BCL6--regulated by AhR/ARNT and wild-type MEF2B--drives expression of germinal center markers MYBL1 and LMO2.
dc.contributor.author | Ding, Jie | |
dc.contributor.author | Dirks, Wilhelm G | |
dc.contributor.author | Ehrentraut, Stefan | |
dc.contributor.author | Geffers, Robert | |
dc.contributor.author | MacLeod, Roderick A F | |
dc.contributor.author | Nagel, Stefan | |
dc.contributor.author | Pommerenke, Claudia | |
dc.contributor.author | Romani, Julia | |
dc.contributor.author | Scherr, Michaela | |
dc.contributor.author | Vaas, Lea A I | |
dc.contributor.author | Zaborski, Margarete | |
dc.contributor.author | Drexler, Hans G | |
dc.contributor.author | Quentmeier, Hilmar | |
dc.date.accessioned | 2016-02-25T14:59:25Z | en |
dc.date.available | 2016-02-25T14:59:25Z | en |
dc.date.issued | 2015-06 | en |
dc.identifier.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 | en |
dc.identifier.issn | 1592-8721 | en |
dc.identifier.pmid | 25769544 | en |
dc.identifier.doi | 10.3324/haematol.2014.120048 | en |
dc.identifier.uri | http://hdl.handle.net/10033/599254 | en |
dc.description.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. | |
dc.language.iso | en | en |
dc.subject.mesh | Adaptor Proteins, Signal Transducing | en |
dc.subject.mesh | Aryl Hydrocarbon Receptor Nuclear Translocator | en |
dc.subject.mesh | Basic Helix-Loop-Helix Transcription Factors | en |
dc.subject.mesh | Biomarkers, Tumor | en |
dc.subject.mesh | Cell Line, Tumor | en |
dc.subject.mesh | DNA-Binding Proteins | en |
dc.subject.mesh | Gene Expression Regulation, Neoplastic | en |
dc.subject.mesh | Germinal Center | en |
dc.subject.mesh | Humans | en |
dc.subject.mesh | LIM Domain Proteins | en |
dc.subject.mesh | Lymphoma, Large B-Cell, Diffuse | en |
dc.subject.mesh | MEF2 Transcription Factors | en |
dc.subject.mesh | Proto-Oncogene Proteins | en |
dc.subject.mesh | Receptors, Aryl Hydrocarbon | en |
dc.subject.mesh | Trans-Activators | en |
dc.title | BCL6--regulated by AhR/ARNT and wild-type MEF2B--drives expression of germinal center markers MYBL1 and LMO2. | en |
dc.type | Article | en |
dc.contributor.department | Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany. | en |
dc.identifier.journal | Haematologica | en |
refterms.dateFOA | 2018-06-12T22:52:16Z | |
html.description.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. |