title: Identification of a new gene regulatory circuit involving B cell receptor activated signaling using a combined analysis of experimental, clinical and global gene expression data.
abstract: To discover new regulatory pathways in B lymphoma cells, we performed a combined analysis of experimental, clinical and global gene expression data. We identified a specific cluster of genes that was coherently expressed in primary lymphoma samples and suppressed by activation of the B cell receptor (BCR) through αIgM treatment of lymphoma cells in vitro. This gene cluster, which we called BCR.1, includes numerous cell cycle regulators. A reduced expression of BCR.1 genes after BCR activation was observed in different cell lines and also in CD10+ germinal center B cells. We found that BCR activation led to a delayed entry to and progression of mitosis and defects in metaphase. Cytogenetic changes were detected upon long-term αIgM treatment. Furthermore, an inverse correlation of BCR.1 genes with c-Myc co-regulated genes in distinct groups of lymphoma patients was observed. Finally, we showed that the BCR.1 index discriminates activated B cell-like and germinal centre B cell-like diffuse large B cell lymphoma supporting the functional relevance of this new regulatory circuit and the power of guided clustering for biomarker discovery.
authors.affiliation: Department of Haematology and Medical Oncology, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany.|GRK1034 of the Deutsche Forschungsgemeinschaft, Georg-August University Göttingen, Göttingen, Germany.|Department of Anatomy, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany.|Present address: Laboratory of Lymphocyte Signaling and Oncoproteome, Department I of Internal Medicine, University Hospital Cologne, Center for Integrated Oncology (CIO) Köln-Bonn, Cologne, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schrader
authors.affiliation: Department of Statistical Bioinformatics, Institute for Functional Genomics, University of Regensburg, Regensburg, Germany.|BMBF-Network HämatoSys, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Meyer
authors.affiliation: Department of Haematology and Medical Oncology, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany.
authors.forename: Neele
authors.initials: N
authors.lastname: Walther
authors.affiliation: Goettingen Center for Molecular Biosciences (GZMB) and University Medical Center, Institute of Molecular Oncology, Section for Cellular Oncology, Göttingen, Germany.
authors.forename: Ailine
authors.initials: A
authors.lastname: Stolz
authors.affiliation: Department of Haematology and Medical Oncology, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany.|BMBF-Network Myc-Sys, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Feist
authors.affiliation: Department of Haematology and Medical Oncology, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany.|BMBF-Network HämatoSys, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hand
authors.affiliation: Department of Haematology and Medical Oncology, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany.
authors.forename: Frederike
authors.initials: F
authors.lastname: von Bonin
authors.affiliation: Department of Statistical Bioinformatics, Institute for Functional Genomics, University of Regensburg, Regensburg, Germany.|BMBF-Network HämatoSys, Germany.|Current address: The John Curtin School of Medical Research the Australian National University Canberra, Australia.
authors.forename: Maurits
authors.initials: M
authors.lastname: Evers
authors.affiliation: Department of Statistical Bioinformatics, Institute for Functional Genomics, University of Regensburg, Regensburg, Germany.|BMBF-Network HämatoSys, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kohler
authors.affiliation: Department of Haematology and Medical Oncology, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany.
authors.forename: Katayoon
authors.initials: K
authors.lastname: Shirneshan
authors.affiliation: Network Molecular Mechanism of Malignant Lymphoma (MMML) of the Deutsche Krebshilfe, Germany.|School of Cancer Sciences, University of Birmingham, Birmingham, UK.|Department of Anatomy, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany.|Present address: Department of Anatomy, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Vockerodt
authors.affiliation: Network Molecular Mechanism of Malignant Lymphoma (MMML) of the Deutsche Krebshilfe, Germany.|BMBF-Network HämatoSys, Germany.|BMBF-Network Myc-Sys, Germany.|University-Hospital Schleswig-Holstein, Hematopathology Section and Lymph Node Registry Kiel, Kiel, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.affiliation: Network Molecular Mechanism of Malignant Lymphoma (MMML) of the Deutsche Krebshilfe, Germany.|BMBF-Network HämatoSys, Germany.|BMBF-Network Myc-Sys, Germany.|University-Hospital Schleswig-Holstein, Hematopathology Section and Lymph Node Registry Kiel, Kiel, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Szczepanowski
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Murray
authors.affiliation: Goettingen Center for Molecular Biosciences (GZMB) and University Medical Center, Institute of Molecular Oncology, Section for Cellular Oncology, Göttingen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Bastians
authors.affiliation: Department of Haematology and Medical Oncology, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany.|GRK1034 of the Deutsche Forschungsgemeinschaft, Georg-August University Göttingen, Göttingen, Germany.|Network Molecular Mechanism of Malignant Lymphoma (MMML) of the Deutsche Krebshilfe, Germany.|BMBF-Network Myc-Sys, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Trümper
authors.affiliation: Department of Statistical Bioinformatics, Institute for Functional Genomics, University of Regensburg, Regensburg, Germany.|Network Molecular Mechanism of Malignant Lymphoma (MMML) of the Deutsche Krebshilfe, Germany.|BMBF-Network HämatoSys, Germany.|BMBF-Network Myc-Sys, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Spang
authors.affiliation: Department of Haematology and Medical Oncology, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany.|GRK1034 of the Deutsche Forschungsgemeinschaft, Georg-August University Göttingen, Göttingen, Germany.|Network Molecular Mechanism of Malignant Lymphoma (MMML) of the Deutsche Krebshilfe, Germany.|BMBF-Network HämatoSys, Germany.|BMBF-Network Myc-Sys, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Kube
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D015331:Cohort Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008213:Lymphocyte Activation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D059016:Tumor Microenvironment
chemical_list: C489427:MYC protein, human; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc; D011947:Receptors, Antigen, B-Cell
keywords: B cell receptor signaling; cell cycle delay; chromosomal aberrations; guided clustering; lymphoma