Showing papers by "Lorenz Trümper published in 2012"
TL;DR: TNFSF7 and TNFSF9 deletions are recurrent genetic lesions in multiple types of human lymphomas, speculate that the deletions may mostly function through a haploinsufficiency mechanism.
Abstract: A single nucleotide polymorphism-chip analysis of 98 cases of aggressive B-cell lymphomas revealed a recurrent deletion at 19p13 in nine of the cases Six further cases with deletions encompassing this region were found in array-comparative genomic hybridization data of 295 aggressive B-cell lymphomas from a previous study Three cases even showed a homozygous deletion, suggesting a tumor suppressor gene in the deleted region Two genes encoding members of the tumor necrosis factor superfamily (TNFSF) were located in the minimally deleted region, that is, TNFSF7 and TNFSF9 As no mutations were found within the coding exons of the remaining alleles in the lymphomas with heterozygous deletions, we speculate that the deletions may mostly function through a haploinsufficiency mechanism The cases with deletions encompassed both diffuse large B-cell lymphomas and Burkitt lymphomas, and a deletion was also found in a Hodgkin lymphoma cell line Thus, TNFSF7 and TNFSF9 deletions are recurrent genetic lesions in multiple types of human lymphomas
31 citations
TL;DR: A critical role is suggested for TNF-TNFR signaling for the clinical outcome of patients with peripheral T-NHLs and Elevations of circulating levels of sTNFRI, IL-10, and sIL-4R are frequent, but the clinical response in these patients is not significantly different.
Abstract: Purpose: Peripheral T-cell non–Hodgkin lymphomas (T-NHL) represent a small but heterogeneous and clinically aggressive subset of NHLs with a poor outcome. Cytokines or their receptors might be associated with the clinical outcome of these lymphomas. Therefore, we tested whether gene variations and serum levels of soluble TNF receptor (TNFR)I (sTNFRI), sTNFRII, interleukin (IL)-10, or sIL-4R are predictive for treatment response in T-NHLs. Experimental Design: Peripheral blood DNA from 117 patients with T-NHL treated in prospective clinical trials was subjected to genotyping analysis. Whenever possible, pretreatment sera were obtained, and circulating levels of sTNFRI, sTNFRII, IL-10, and sIL-4R were determined with a specific capture enzyme-linked immunoassay. Results: Patients characterized by TNFRI-609GG (rs4149570) showed a trend toward better event free survival [EFS; univariate: P = 0.041; multivariate: HR, 1.76; confidence interval (CI), 0.99–3.14 with P = 0.056]. A protective role of IL-10–1087A , − 824T , and − 597A reported in another study was not confirmed in our cohort. Patients with circulating levels of soluble TNFRII ≥2.16 ng/mL had a 2.07-fold increased relative risk for shorter overall survival (OS; univariate: P = 0.0034; multivariate: HR, 2.07; CI, 0.92–4.70 with P = 0.081) and a 2.49-fold higher risk for shorter EFS (univariate: P = 0.00068; multivariate: HR, 2.49; CI, 1.22–5.08 with P = 0.012). Elevations of circulating levels of sTNFRI, IL-10, and sIL-4R are frequent, but the clinical response in these patients is not significantly different. Conclusions: Our findings suggest a critical role for TNF-TNFR signaling for the clinical outcome of patients with peripheral T-NHLs. Clin Cancer Res; 18(13); 3637–47. ©2012 AACR .
29 citations
TL;DR: The extent to which different immune response associated pathways are responsible for differences in gene expression which distinguish individual DLBCL cases is defined and the view that tonic or constitutively active MAPK/ERK pathways are an important part of oncogenic signalling in NHL is supported.
Abstract: 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). α 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 αIgM. 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 αIgM 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 αIgM gene module. 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.
18 citations
TL;DR: Overall survival at 3 years was 42% (95% CI, 31% to 52%), progression-free survival (PFS) was 40% ( 95% CI 29% to 50%).
Abstract: 8004 Background: The role of allogeneic stem cell transplantation (alloSCT) in high-risk aggressive NHL is poorly defined; the role of graft-versus-lymphoma effect is unclear. Reduced intensity con...
5 citations
TL;DR: FISH analysis of circulating CD34+ pb cells provides relevant cytogenetic informations in patients with MDS during the course of disease and under different therapies, and helps in cases where a bm biopsy is not possible or not successful.
2 citations
TL;DR: The primary end point was overall response rate (ORR), as assessed by an independent end points review committee, and secondary end points included complete response (CR), progression-free survival (PFS), overall survival, adverse events (AEs) and PK.
1 citations