Filters
Technology
Platform
GSE45495
Homo sapiens
16 Downloadable Samples
Illumina HumanHT-12 V4.0 expression beadchip
Description
Diffuse large B-cell lymphoma (DLBCL) represents a heterogeneous diagnostic category with distinct molecular subtypes that can be defined by gene expression profiling. However, even within these defined subtypes, heterogeneity prevails. To further elucidate the pathogenesis of these entities, we determined the expression of the tumor suppressor phosphatase and tensin homolog (PTEN) in 248 primary DLBCL patient samples. These analyses revealed that loss of PTEN was detectable in 55% of germinal center B-cell-like (GCB) DLBCLs, whereas this abnormality was found in only 14% of non-GCB DLBCL patient samples. In GCB DLBCL, the PTEN status was inversely correlated with activation of the oncogenic PI3K/ protein kinase B (AKT) pathway in both DLBCL cell lines and primary patient samples. Re-expression of PTEN induced cytotoxicity in PTEN-deficient GCB DLBCL cell line models by inhibiting PI3K/AKT signaling, indicating an addiction to this pathway in this subset of GCB DLBCLs. PI3K/AKT inhibition induced down-regulation of the transcription factor MYC. Re-expression of MYC rescued GCB DLBCL cells from PTEN-induced toxicity, identifying a regulatory mechanism of MYC expression in DLBCL. Finally, pharmacologic PI3K inhibition resulted in toxicity selectively in PTEN-deficient GCB DLBCL lines. Collectively, our results indicate that PTEN loss defines a PI3K/ AKT-dependent GCB DLBCL subtype that is addicted to PI3K and MYC signaling and suggest that pharmacologic inhibition of PI3K might represent a promising therapeutic approach in these lymphomas.
Publication Title
PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma.
Sample Metadata Fields
Sex, Disease, Cell line, Treatment
View Samples- Homo sapiens
- 40 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Activated B-cell-like (ABC) and germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) represent the two major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these two subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) alpha/delta (PI3Ka/d) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor kappa-B (NF-kB) signaling, prompting us to combine AZD8835 with the Brutons tyrosine kinase (BTK) inhibitor ibrutinib. This combination was highly synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.
Publication Title
Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 36 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by poor clinical outcome. Recent studies revealed the importance of BCR signaling in maintaining MCL survival. However, it remains unclear which role MALT1, an essential component of the CARD11-BCL10-MALT1 (CBM) complex that transfers BCR signaling to the NF-kB pathway, plays in the biology of MCL. Here we show that a subset of MCLs is addicted to MALT1, as its inhibition by either RNA or pharmacologic interference induced cytotoxicity both in vitro and in vivo. Gene expression profiling following MALT1 inhibition demonstrated that MALT1 controls a MYC-driven gene expression network predominantly through increased MYC protein stability. Thus our analyses identify a previously unappreciated regulatory mechanism of MYC expression. Investigating primary mouse splenocytes, we could demonstrate that MALT1 induced MYC regulation is not restricted to MCL, but represents a common mechanism of MYC regulation. MYC itself is pivotal for MCL survival as its downregulation and pharmacologic inhibition induced cytotoxicity in all MCL models. Collectively, these results provide a strong mechanistic rationale to investigate the therapeutic efficacy in targeting the MALT1-MYC axis in MCL patients.
Publication Title
B-cell receptor-driven MALT1 activity regulates MYC signaling in mantle cell lymphoma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 25 Downloadable Samples
Illumina HumanHT-12 V4.0 expression beadchip, Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 26 Downloadable Samples
- Affymetrix Human Gene 1.1 ST Array (hugene11st)
Description
Tumor-induced immunosuppression remains a major challenge for immunotherapy of cancer patients. To further elucidate why an allogeneic gene-modified (Interleukin-7(IL-7)/CD80 co-transfected) renal cell cancer vaccine failed to induce clinically relevant TH1-polarized immune responses, peripheral blood mononuclear cells (PBMCs) from enrolled study patients were analyzed by gene expression profiling (GEP) both prior and after vaccination. At baseline before vaccination, a profound downregulation of gene signatures associated with antigen presentation, immune response/T cells, cytokines/chemokines and signaling/transcription factors was observed in renal cell cancer patients as compared to healthy controls. Vaccination led to a partial reversion of preexisting immunosuppression, however, GEP indicated that an appropriate TH1 polarization could not be achieved. Most interestingly, our results suggest that the nuclear factor kappa B (NF-B) signaling pathway might be involved in the impairment of immunological responsiveness and the observed TH2 deviation. In summary, our data suggest that GEP might be a powerful tool for the prediction of immunosuppression and the monitoring of immune responses within immunotherapy trials.
Publication Title
Gene expression profiling of peripheral blood mononuclear cells during treatment with a gene-modified allogeneic tumor cell vaccine in advanced renal cell cancer: tumor-induced immunosuppression and a possible role for NF-κB.
Sample Metadata Fields
Treatment
View Samples- Homo sapiens
- 24 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Three ALCL cell lines DEL, FEPD and K299 were induced with an IRF4-specific shRNA for up to 96 hours.
Publication Title
Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
In human chronic lymphocytic leukemia (CLL) pathogenesis B cell antigen receptor signaling seems important for leukemia B cell ontogeny, whereas the microenvironment influences B cell activation, tumor cell lodging and provision of antigenic stimuli. Using the murine E-Tcl1 CLL model, we demonstrate that CXCR5-controlled access to follicular dendritic cells (FDCs) confers proliferative stimuli to leukemia B cells. Intravital imaging revealed a marginal zone B cell-like leukemia cell trafficking route. Murine and human CLL cells reciprocally stimulated resident mesenchymal stromal cells through lymphotoxin--receptor activation, resulting in CXCL13 secretion and stromal compartment remodeling. Inhibition of lymphotoxin/lymphotoxin--receptor signaling or of CXCR5 signaling retards leukemia progression. Thus, CXCR5 activity links tumor cell homing, shaping a survival niche, and access to localized proliferation stimuli.
Publication Title
Access to follicular dendritic cells is a pivotal step in murine chronic lymphocytic leukemia B-cell activation and proliferation.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 13 Downloadable Samples
- Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version), Illumina HumanHT-12 V4.0 expression beadchip
Description
Constitutive activation of the nuclear factor-kappa B (NF-kB) pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Recurrent mutations of NF-kB regulators that cause constitutive activity of this oncogenic pathway have been identified. However, it remains unclear how specific target genes are regulated. We identified the IkB-like protein NFKBIZ that binds NF-kB subunits and enhances transactivation of some NF-kB target genes while repressing others, to be upregulated in ACB compared to GCB DLBCL primary patient samples (p=5.1 x 10^-37). Knockdown of NFKBIZ by RNA interference was toxic to ABC but not GCB DLBCL cell lines. Gene expression profiling following NFKBIZ knockdown significantly downregulated a large number of NF-kB target genes, suggesting a central role in regulating NF-kB signaling. To further investigate the molecular mechanisms of how NFKBIZ mediates NF-kB signaling in ABC DLBCL, we performed immunoprecipitations and detected an interaction of NFKBIZ with both p50 and p52 NF-kB subunits, indicating that both the canonical and non-canonical NF-kB pathways are regulated by NFKBIZ. Collectively, our data imply that NFKBIZ is required for NF-kB signaling in ABC DLBCL and thus might represent a promising molecular target for future therapies.
Publication Title
IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Monocyte chemoattractant protein 1 (MCP-1/CCL2) is critically involved in directing the migration of blood monocytes to sites of inflammation. Consequently, excessive MCP-1 secretion has been linked to many (auto)inflammatory diseases, whereas a lack of expression severely impairs immune responsiveness. We demonstrate that the atypical inhibitor of NF-B (IB), a transcriptional co-activator required for the selective expression of a subset of NF-B target genes, is a key activator of the Ccl2 gene. IB-deficient macrophages exhibited impaired secretion of MCP-1 when challenged with diverse inflammatory stimuli, such as lipopolysaccharide or peptidoglycan. These findings were reflected at the level of Ccl2 gene expression, which was tightly coupled to the presence of IB. Moreover, mechanistic insights acquired by chromatin immunoprecipitation demonstrate that IB is directly recruited to the proximal promoter region of the Ccl2 gene and required for histone H3K9 trimethylation. Finally, IB-deficient mice showed significantly impaired MCP-1 secretion and monocyte infiltration in an experimental model of peritonitis. Together, these findings suggest a distinguished role of IB in mediating the targeted recruitment of monocytes in response to local inflammatory events.
Publication Title
IκBζ is a transcriptional key regulator of CCL2/MCP-1.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 12 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Constitutive activation of the nuclear factor-kappa B (NF-kB) pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Recurrent mutations of NF-kB regulators that cause constitutive activity of this oncogenic pathway have been identified. However, it remains unclear how specific target genes are regulated. We identified the IkB-like protein NFKBIZ that binds NF-kB subunits and enhances transactivation of some NF-kB target genes while repressing others, to be upregulated in ACB compared to GCB DLBCL primary patient samples (p=5.1 x 10^-37). Knockdown of NFKBIZ by RNA interference was toxic to ABC but not GCB DLBCL cell lines. Gene expression profiling following NFKBIZ knockdown significantly downregulated a large number of NF-kB target genes, suggesting a central role in regulating NF-kB signaling. To further investigate the molecular mechanisms of how NFKBIZ mediates NF-kB signaling in ABC DLBCL, we performed immunoprecipitations and detected an interaction of NFKBIZ with both p50 and p52 NF-kB subunits, indicating that both the canonical and non-canonical NF-kB pathways are regulated by NFKBIZ. Collectively, our data imply that NFKBIZ is required for NF-kB signaling in ABC DLBCL and thus might represent a promising molecular target for future therapies.
Publication Title
IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL.
Sample Metadata Fields
Cell line, Treatment
View Samples