Schrader, Alexandra and Meyer, Katharina and von Bonin, Frederike and Vockerodt, Martina and Walther, Neele and Hand, Elisabeth and Ulrich, Antje and Matulewicz, Kamila and Lenze, Dido and Hummel, Michael and Kieser, Arnd and Engelke, Michael and Truemper, Lorenz and Kube, Dieter (2012) 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. CELL COMMUNICATION AND SIGNALING, 10: 43. ISSN 1478-811X,
Full text not available from this repository. (Request a copy)Abstract
Background: 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). Methodology: 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-kappa B, 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). Results: alpha IgM stimulation led to the largest number of changes in gene expression, affecting overall 6596 genes. While CD40L stimulation changed the expression of 1194 genes and IL21 stimulation affected 902 genes, only 283 and 129 genes were modulated by lipopolysaccharide or BAFF receptor stimulation, respectively. Interestingly, genes associated with a Burkitt-like phenotype, such as MYC, BCL6 or LEF1, were affected by alpha IgM. Unique and shared gene expression was delineated. NHL-patients were sorted according to their similarity in the expression of TOP100 affected genes to stimulated transformed germinal centre B cells The alpha IgM gene module discriminated individual DLBCL in a similar manner to CD40L or IL21 gene modules. DLBCLs with low module activation often carry chromosomal MYC aberrations. DLBCLs with high module activation show strong expression of genes involved in cell-cell communication, immune responses or negative feedback loops. Using chemical inhibitors for selected kinases we show that mitogen activated protein kinase-and phosphoinositide 3 kinase-signalling are dominantly involved in regulating genes included in the alpha IgM gene module. Conclusion: 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NF-KAPPA-B; DISTINCT TYPES; SURVIVAL; SIGNATURES; INHIBITION; PREDICTS; SUBTYPES; CCR7; DIFFERENTIATION; PROLIFERATION; Gene expression pattern; Lymphoma; Pathway activation |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Statistische Bioinformatik (Prof. Spang) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Apr 2020 07:28 |
| Last Modified: | 30 Apr 2020 07:28 |
| URI: | https://pred.uni-regensburg.de/id/eprint/17584 |
Actions (login required)
 |
View Item |
