In Burkitt lymphoma (BL), an aggressive germinal-center (GC) derived non-Hodgkin B-cell lymphoma characterized by MYC translocations as early transforming event, the apoptotic properties of MYC must have been overcome by pro-survival signals. Whereas activation of the pro-survival factor NFkappaB is not eminent in BL, PI3K signalling, which mediates B cell receptor associated survival signals in mature B cells, might be the cooperating event. Here we prove this hypothesis by the generation of BL in mice upon concordant expression of MYC and activation of PI3K in GC B cells. Unlike existing murine BL-like models, our tumour model fully phenocopies primary human BL and reflects the complexity of the disease with regard to histological appearance, surface marker expression, and characteristic gene expression profiles. Like in human BL, tumour monoclonality indicated a multistep pathogenesis underlining MYC and PI3K as predisposing events that invariably lead to GC-derived BL formation. In accordance, copy number alteration analysis revealed genomic regions involved in BL pathogenesis.
Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis.
Specimen part
View SamplesGenomewide gene expression analysis of lymphoid cell lines of Hodgkin, non-Hodgkin and acute leukemia origin
High-level expression of Mastermind-like 2 contributes to aberrant activation of the NOTCH signaling pathway in human lymphomas.
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View SamplesGenome-wide gene expression analysis of Reh cells following transfection with constitutively active IRF5-4D, constitutively active IKK(EE), or both in combination.
Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma.
Cell line
View SamplesGenome-wide gene expression analysis of Reh cells following transfection with shRNA targeting CBFA2T3, constitutively active IKK(EE), or both in combination.
Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma.
Cell line
View SamplesGenome-wide gene expression analysis of murine splenic B-cells following retroviral transduction with a constitutively active IRF5 (IRF5-4D)
Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma.
Specimen part
View SamplesThe complex response of murine macrophages to infection with Streptococcus pyogenes was investigated at the level of gene expression using a high-density oligomer microarray. More than 400 genes were identified as being differentially regulated. Many of the up-regulated genes encoded molecules were involved in immune response and inflammation, transcription, signalling, apoptosis, cell cycle, electron transport and cell adhesion. Of particular interest was the up-regulation of proinflammatory cytokines, typical of the classically activated macrophages (M1 phenotype) such as TNF-?, IL-1 and IL-6, and also the up-regulation of anti-inflammatory mediators such as IL-1ra and IL-10 associated with macrophage alternative activation (M2 phenotype). Furthermore, the gene encoding inducible nitric oxide synthase (iNOS), an enzyme typically implicated in classical activation was not induced in infected macrophages. Instead, the gene encoding arginase, a competitor for the iNOS substrate arginine and involved in the alternative activation pathway was up-regulated in S. pyogenes-infected cells. Thus, the microarray-based gene expression analysis demonstrated that S. pyogenes induced an atypical activation program in macrophages with some but not all features of classically or alternatively activation phenotypes. The microarray data also suggested that the bactericidal activity of macrophages against S. pyogenes is mediated by phagocyte oxydase since p47phox was up-regulated in infected cells. Indeed, the in vivo and in vitro killing of S. pyogenes was markedly diminished in the absence of functional phagocyte (p47phox-/-) but not in the absence of iNOS (iNOS-/-). Understanding how macrophages respond to S. pyogenes at the molecular level may facilitate the development of new therapeutic paradigms.
Transcriptome analysis of murine macrophages in response to infection with Streptococcus pyogenes reveals an unusual activation program.
Specimen part
View SamplesWe disprove that the impaired Myd88-dependent proinflammatory response of neonatal monocytes is a correlate for immaturity and confirm it as display of transient alarmin-mediated stress tolerization. We find a strong inducibility of TRIF-dependent genes in neonatal monocytes by LPS but a barely detectable expression at baseline.
S100-alarmin-induced innate immune programming protects newborn infants from sepsis.
Specimen part, Treatment
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