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
| Autor: | Lorenz Trümper, Ailine Stolz, Paul Murray, Katayoon Shirneshan, Alexandra Schrader, Maurits Evers, Monika Szczepanowski, Holger Bastians, Wolfram Klapper, Dieter Kube, Frederike von Bonin, Katharina Meyer, Rainer Spang, Neele Walther, Elisabeth Hand, Christian W. Kohler, Maren Feist, Martina Vockerodt |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology 610 Medizin Lymphocyte Activation cell cycle delay Cohort Studies 0302 clinical medicine hemic and lymphatic diseases Gene expression Tumor Microenvironment Gene Regulatory Networks ddc:610 B-Lymphocytes Hematology guided clustering Cell Cycle 3. Good health Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis Proto-Oncogene Proteins c-bcl-6 lymphoma B cell receptor signaling chromosomal aberrations Regulatory circuit Lymphoma Large B-Cell Diffuse Research Paper Signal Transduction ddc:500 medicine.medical_specialty B-cell receptor Receptors Antigen B-Cell Proto-Oncogene Proteins c-myc 03 medical and health sciences Internal medicine Cell Line Tumor medicine Humans Gene business.industry Gene Expression Profiling Germinal center medicine.disease Germinal Center Lymphoma 030104 developmental biology Immunology 500 Naturwissenschaften business Diffuse large B-cell lymphoma |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Alexandra Schrader 1, 2, 10, 11 , Katharina Meyer 3, 6 , Neele Walther 1 , Ailine Stolz 4 , Maren Feist 1, 7 , Elisabeth Hand 1, 6 , Frederike von Bonin 1 , Maurits Evers 3, 6, 13 , Christian Kohler 3, 6 , Katayoon Shirneshan 1 , Martina Vockerodt 5, 8, 10, 12 , Wolfram Klapper 5, 6, 7, 9 , Monika Szczepanowski 5, 6, 7, 9 , Paul G. Murray 8 , Holger Bastians 4 , Lorenz Trumper 1, 2, 5, 7 , Rainer Spang 3, 5, 6, 7 , Dieter Kube 1, 2, 5, 6, 7 1 Department of Haematology and Medical Oncology, University Medical Centre of the Georg-August University Gottingen, Gottingen, Germany 2 GRK1034 of the Deutsche Forschungsgemeinschaft, Georg-August University Gottingen, Gottingen, Germany 3 Department of Statistical Bioinformatics, Institute for Functional Genomics, University of Regensburg, Regensburg, Germany 4 Goettingen Center for Molecular Biosciences (GZMB) and University Medical Center, Institute of Molecular Oncology, Section for Cellular Oncology, Gottingen, Germany 5 Network Molecular Mechanism of Malignant Lymphoma (MMML) of the Deutsche Krebshilfe, Germany 6 BMBF-Network HamatoSys, Germany 7 BMBF-Network Myc-Sys, Germany 8 School of Cancer Sciences, University of Birmingham, Birmingham, UK 9 University-Hospital Schleswig-Holstein, Hematopathology Section and Lymph Node Registry Kiel, Kiel, Germany 10 Department of Anatomy, University Medical Centre of the Georg-August University Gottingen, Gottingen, Germany 11 Present address: Laboratory of Lymphocyte Signaling and Oncoproteome, Department I of Internal Medicine, University Hospital Cologne, Center for Integrated Oncology (CIO) Koln-Bonn, Cologne, Germany 12 Present address: Department of Anatomy, University Medical Centre of the Georg-August University Gottingen, Gottingen, Germany 13 Current address: The John Curtin School of Medical Research the Australian National University Canberra, Australia Correspondence to: Dieter Kube, e-mail: dieter.kube@med.uni-goettingen.de Keywords: lymphoma, B cell receptor signaling, guided clustering, cell cycle delay, chromosomal aberrations Received: September 23, 2015 Accepted: March 31, 2016 Published: May 7, 2016 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. |
| Databáze: | OpenAIRE |
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