Global gene expression changes of in vitro stimulated human transformed germinal centre B cells as surrogate for oncogenic pathway activation in individual aggressive B cell lymphomas
1 Department of Haematology and Oncology, University Medical Centre Göttingen, Göttingen, Germany
2 Computational Diagnostics Group, Institute for Functional Genomics, University of Regensburg, Regensburg, Germany
3 School of Cancer Sciences, University of Birmingham, Birmingham, UK
4 Institute for Pathology, Campus Benjamin Franklin Charité Berlin, Berlin, Germany
5 Research Unit Gene Vectors, Helmholtz Zentrum München - German Research Center for Environmental Health, München, Germany
6 Department of Cellular and Molecular Immunology, University Medical Centre Göttingen, Göttingen, Germany
7 Network “Molecular Mechanism of Malignant Lymphoma” (MMML) of the Deutsche Krebshilfe, Göttingen, Germany
8 FOR942 of the Deutsche Forschungsgemeinschaft at the University Medical Centre Göttingen, Göttingen, Germany
9 GRK 1034 of the Deutsche Forschungsgemeinschaft, Göttingen, Germany
10 Network HaematoSys, Leipzig, Germany
11 Department of Pediatrics I, University Medical Centre Göttingen, Göttingen, Germany
12 Zentrum für Innere Medizin, Abteilung Hämatologie und Onkologie, Universitätsmedizin der Georg-August-Universität Göttingen, 37099, Göttingen, Germany
Cell Communication and Signaling 2012, 10:43 doi:10.1186/1478-811X-10-43Published: 20 December 2012
Aggressive Non-Hodgkin lymphomas (NHL) are a group of lymphomas derived from germinal centre B cells which display a heterogeneous pattern of oncogenic pathway activation. We postulate that specific immune response associated signalling, affecting gene transcription networks, may be associated with the activation of different oncogenic pathways in aggressive Non-Hodgkin lymphomas (NHL).
The B cell receptor (BCR), CD40, B-cell activating factor (BAFF)-receptors and Interleukin (IL) 21 receptor and Toll like receptor 4 (TLR4) were stimulated in human transformed germinal centre B cells by treatment with anti IgM F(ab)2-fragments, CD40L, BAFF, IL21 and LPS respectively. The changes in gene expression following the activation of Jak/STAT, NF-кB, MAPK, Ca2+ and PI3K signalling triggered by these stimuli was assessed using microarray analysis. The expression of top 100 genes which had a change in gene expression following stimulation was investigated in gene expression profiles of patients with Aggressive non-Hodgkin Lymphoma (NHL).
We provide an in vitro model system to investigate pathway activation in lymphomas. We defined the extent to which different immune response associated pathways are responsible for differences in gene expression which distinguish individual DLBCL cases. Our results support the view that tonic or constitutively active MAPK/ERK pathways are an important part of oncogenic signalling in NHL. The experimental model can now be applied to study the therapeutic potential of deregulated oncogenic pathways and to develop individual treatment strategies for lymphoma patients.