title: BCL6--regulated by AhR/ARNT and wild-type MEF2B--drives expression of germinal center markers MYBL1 and LMO2.
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.
authors.affiliation: Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig.
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.affiliation: Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig.
authors.forename: Wilhelm G
authors.initials: WG
authors.lastname: Dirks
authors.affiliation: Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehrentraut
authors.affiliation: Helmholtz Centre for Infection Research, Genome Analysis Research Group, Braunschweig.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig.
authors.forename: Roderick A F
authors.initials: RA
authors.lastname: MacLeod
authors.affiliation: Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig.
authors.forename: Stefan
authors.initials: S
authors.lastname: Nagel
authors.affiliation: Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pommerenke
authors.affiliation: Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig.
authors.forename: Julia
authors.initials: J
authors.lastname: Romani
authors.affiliation: Medical School Hannover, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.affiliation: Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig.
authors.forename: Lea A I
authors.initials: LA
authors.lastname: Vaas
authors.affiliation: Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig.
authors.forename: Margarete
authors.initials: M
authors.lastname: Zaborski
authors.affiliation: Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Drexler
authors.affiliation: Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig hqu@dsmz.de.
authors.forename: Hilmar
authors.initials: H
authors.lastname: Quentmeier
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000502:physiology; D006801:Humans; D060588:LIM Domain Proteins / Q000096:biosynthesis / Q000235:genetics*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D064326:MEF2 Transcription Factors; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D018336:Receptors, Aryl Hydrocarbon; D015534:Trans-Activators; C111235:AHR protein, human; C497396:ARNT protein, human; C084103:BCL6 protein, human; C085117:LMO2 protein, human; C578038:MEF2B protein, human; C088831:MYBL1 protein, human