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
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Alexandra Schrader1,2,10,11, Katharina Meyer3,6, Neele Walther1, Ailine Stolz4, Maren Feist1,7, Elisabeth Hand1,6, Frederike von Bonin1, Maurits Evers3,6,13, Christian Kohler3,6, Katayoon Shirneshan1, Martina Vockerodt5,8,10,12, Wolfram Klapper5,6,7,9, Monika Szczepanowski5,6,7,9, Paul G. Murray8, Holger Bastians4, Lorenz Trümper1,2,5,7, Rainer Spang3,5,6,7, Dieter Kube1,2,5,6,7
1Department of Haematology and Medical Oncology, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany
2GRK1034 of the Deutsche Forschungsgemeinschaft, Georg-August University Göttingen, Göttingen, Germany
3Department of Statistical Bioinformatics, Institute for Functional Genomics, University of Regensburg, Regensburg, Germany
4Goettingen Center for Molecular Biosciences (GZMB) and University Medical Center, Institute of Molecular Oncology, Section for Cellular Oncology, Göttingen, Germany
5Network Molecular Mechanism of Malignant Lymphoma (MMML) of the Deutsche Krebshilfe, Germany
6BMBF-Network HämatoSys, Germany
7BMBF-Network Myc-Sys, Germany
8School of Cancer Sciences, University of Birmingham, Birmingham, UK
9University-Hospital Schleswig-Holstein, Hematopathology Section and Lymph Node Registry Kiel, Kiel, Germany
10Department of Anatomy, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany
11Present address: Laboratory of Lymphocyte Signaling and Oncoproteome, Department I of Internal Medicine, University Hospital Cologne, Center for Integrated Oncology (CIO) Köln-Bonn, Cologne, Germany
12Present address: Department of Anatomy, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany
13Current address: The John Curtin School of Medical Research the Australian National University Canberra, Australia
Dieter Kube, e-mail: [email protected]
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
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.
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