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

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

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)47061-47081
Number of pages21
JournalOncoTarget
Volume7
Issue number30
DOIs
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

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