Anaplastic Large Cell Lymphomas (ALCL) represent a subset of lymphomas in which the Anaplastic Lymphoma Kinase (ALK) gene is frequently fused to the NPM gene. We previously demonstrated that the constitutive phosphorylation of ALK chimeric proteins is sufficient to induce cellular transformation in vitro and in vivo, and that ALK activity is strictly required for the survival of ALK positive ALCL cells. To elucidate the signaling pathways required for ALK-mediated transformation and tumor maintenance, we analyzed the transcriptomes of multiple ALK positive ALCL cell lines abrogating their ALK-mediated signaling by inducible ALK RNA interference (RNAi) or with potent and cell permeable ALK inhibitors. Transcripts derived from the gene expression profiling (GEP) analysis uncovered a reproducible signature, which included a novel group of ALK-regulated genes. Functional RNAi screening on a set of these ALK transcriptional targets revealed that the transcription factor C/EBPb and the anti-apoptotic protein BCL2A1 are absolutely necessary to induce cell transformation and/or to sustain the growth and survival of ALK positive ALCL cells. Thus, we proved that an experimentally controlled and functionally validated GEP analysis represents a powerful tool to identify novel pathogenetic networks and validate biologically suitable target genes for therapeutic interventions.
Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and BCL2A1 as critical target genes.
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View SamplesAnalysis of mRNA expression of influenza infected and uninfected pulmonary epithelial cells in vivo Overall design: Analysis of mRNA expression of influenza infected and uninfected pulmonary epithelial cells in vivo
Long-term survival of influenza virus infected club cells drives immunopathology.
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View SamplesThis SuperSeries is composed of the SubSeries listed below.
Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory.
Specimen part
View SamplesDuring acute viral infections, nave CD8+ T cells differentiate into effector CD8+ T cells and, after viral control, into memory CD8+ T cells. Memory CD8+ T cells are highly functional, proliferate rapidly upon reinfection and persist long-term without antigen. In contrast, during chronic infections, CD8+ T cells become exhausted and have poor effector function, express multiple inhibitory receptors, possess low proliferative capacity, and cannot persist without antigen. To compare the development of functional memory T cells with poorly functional exhausted T cells, we generated longitudinal transcriptional profiles for each.
Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory.
Specimen part
View SamplesSubstantial experimental evidence has shown that dedifferentiation from an epithelial state to a mesenchymal-like state (EMT) drives tumor cell metastasis. This transition facilitates tumor cells to acquire motility and invasive features. Intriguingly, tumor cells at the metastatic site are primarily epithelial, and it is believed that they re-differentiate back to an epithelial state by a process called mesenchymal to epithelial transition (MET). However, there is little in vivo evidence to support the MET process.
E-cadherin re-expression shows in vivo evidence for mesenchymal to epithelial transition in clonal metastatic breast tumor cells.
Specimen part, Cell line
View SamplesThe role of antibody and B cells in preventing infection is established. In contrast, the role of B cell responses in containing chronic infections remains poorly understood. IgG2a (IgG1 in humans) can prevent acute infections and T-bet promotes IgG2a isotype switching. However, whether IgG2a and B cell-expressed T-bet influence the host-pathogen balance during persisting infections is unclear. Here we demonstrate that B cell specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells not only controlled IgG2a production, but also mucosal localization, proliferation, glycosylation, and a broad transcriptional program. T-bet controlled a broad antiviral program in addition to IgG2a since T-bet in B cells was important even in the presence of virus-specific IgG2a. Our data supports a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages.
Cutting Edge: B Cell-Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection.
Specimen part
View SamplesWe sequenced the total mRNA from infected cells and detected differences in the expression of both host mRNA. We detected a small but significant suppression of T cell activation-related genes at 12 hpi. This suppression persisted and expanded by 24 hpi providing new possible markers of virus-induced T cell cytopathology. By 24 hpi the expression of over 50% of detectable host loci was also altered indicating widespread alteration of host processes including RNA processing, splicing, and transport to an extent not previously reported. In addition next-generation sequencing provided insights into the expression of non-coding RNAs including microRNA host genes. Overall design: We isolated polyadenylated RNA from SUPT1 cells infected with HIV-1 strain LAI at 12 and 24 hours post-infection (3 replicates for each time point). As controls we isolated polyadenylated RNA from mock-infected cells at 12 and 24 hours post-infection (2 replicates at 12 hours post-infection, 3 replicates at 24 hours post-infection).
Next-generation sequencing reveals HIV-1-mediated suppression of T cell activation and RNA processing and regulation of noncoding RNA expression in a CD4+ T cell line.
Cell line, Subject, Time
View SamplesPompe disease is a genetic disorder resulting from a deficiency of lysosomal acid alpha-glucosidase (GAA) that manifests as a clinical spectrum with regard to symptom severity and rate of progression. In this study, we used microarrays to examine gene expression from the muscle of two cohorts of infantile-onset Pompe patients to identify transcriptional differences that may contribute to the disease phenotype. We found strong similarities among the gene expression profiles generated from biceps and quadriceps, and identified a number of signaling pathways altered in both cohorts. We also found that infantile-onset Pompe patient muscle had a gene expression pattern characteristic of immature or regenerating muscle, and exhibited many transcriptional markers of inflammation, despite having few overt signs of inflammatory infiltrate. Further, we identified genes exhibiting correlation between expression at baseline and response to therapy. This combined dataset can serve as a foundation for biological discovery and biomarker development to improve the treatment of Pompe disease.
Transcriptional response to GAA deficiency (Pompe disease) in infantile-onset patients.
Sex, Specimen part, Disease, Treatment, Subject
View SamplesMicroarray expression analysis of mouse ESCs treated with the MYCi 10058-F4.
Myc Depletion Induces a Pluripotent Dormant State Mimicking Diapause.
Specimen part
View SamplesWe used microarrays to identify genes differentially expressed in EBV-infected human B cells supporting lytic replication vs. those refractory to EBV lytic replication.
Signal transducer and activator of transcription 3 limits Epstein-Barr virus lytic activation in B lymphocytes.
Specimen part
View Samples