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

Research output: Contribution to journalArticle

Authors

  • Alexandra Schrader
  • Katharina Meyer
  • Neele Walther
  • Ailine Stolz
  • Maren Feist
  • Elisabeth Hand
  • Frederike von Bonin
  • Maurits Evers
  • Christian Kohler
  • Katayoon Shirneshan
  • Wolfram Klapper
  • Monika Szczepanowski
  • Holger Bastians
  • Lorenz Trümper
  • Rainer Spang
  • Dieter Kube

Colleges, School and Institutes

External organisations

  • 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.
  • BMBF-Network HämatoSys, Germany.
  • Department of Haematology and Medical Oncology, University Medical Centre of the Georg-August University Göttingen, Göttingen, Germany.
  • Goettingen Center for Molecular Biosciences (GZMB) and University Medical Center, Institute of Molecular Oncology, Section for Cellular Oncology, Göttingen, Germany.
  • BMBF-Network Myc-Sys, Germany.
  • Current address: The John Curtin School of Medical Research the Australian National University Canberra, Australia.
  • Network Molecular Mechanism of Malignant Lymphoma (MMML) of the Deutsche Krebshilfe, Germany.
  • School of Cancer Sciences, University of Birmingham g.middleton@bham.ac.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.
  • University-Hospital Schleswig-Holstein, Hematopathology Section and Lymph Node Registry Kiel, Kiel, Germany.

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.

Details

Original languageEnglish
Pages (from-to)47061-47081
Number of pages21
JournalOncoTarget
Volume7
Issue number30
Publication statusPublished - 7 May 2016

Keywords

  • B-Lymphocytes/metabolism, Cell Cycle/genetics, Cell Line, Tumor, Cohort Studies, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Germinal Center/metabolism, Humans, Lymphocyte Activation, Lymphoma, Large B-Cell, Diffuse/genetics, Proto-Oncogene Proteins c-bcl-6, Proto-Oncogene Proteins c-myc, Receptors, Antigen, B-Cell/genetics, Signal Transduction/genetics, Tumor Microenvironment