Genome-wide analysis of gene expression response to MI-2 and z-VRPR-fmk in ABC-DLBCL cell lines
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Lorena Fontan
PROVIDER: E-GEOD-40003 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:MALT1 Small Molecule Inhibitors Specifically Suppress ABC-DLBCL In Vitro and In Vivo
2012-12-11 | GSE40003 | GEO
Project description:A key element for the development of suitable anti-cancer drugs is the identification of cancer-specific enzymatic activities that can be therapeutically targeted. Mucosa-associated lymphoid tissue transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL. Recent data suggest that MALT1 has proteolytic activity, but it is unknown whether this activity is relevant for tumor growth. Here we report that MALT1 is constitutively active in DLBCL lines of the ABC but not the GCB subtype. Inhibition of the MALT1 proteolytic activity led to reduced expression of growth factors and apoptosis inhibitors, and specifically affected the growth and survival of ABC DLBCL lines. These results demonstrate a key role for the proteolytic activity of MALT1 in DLBCL of the ABC subtype, and provide a rationale for the development of pharmacological inhibitors of MALT1 in DLBCL therapy. HBL-1 cells (n=8) were treated with IkB kinase beta inhibitor MLN120B (25 micromolar; Calbiochem) for 2h, 3h, 4h, 6h, 8h, 12h, 16h, and 24h (Cy5) and their gene expression compared to vehicle-treated cells (DMSO, Cy3). HBL-1 cells (n=4) and OCI-Ly3 cells (n=4) were treated with MALT1 inhibitor z-VRPR-fmk (50 micromolar; Alexis Biochemicals) for 6h, 12h, 24h, and 30h (Cy5) and their gene expression compared to vehicle-treated cells (DMSO, Cy3).
2012-09-20 | E-GEOD-41034 | biostudies-arrayexpress
Project description:Interferon regulatory factor 4 (IRF4) is a transcriptional regulator with critical roles in the normal development and malignant transformation of lymphocytes. Recently we have shown that plasma cell cancers (multiple myeloma, MM) are addicted to an aberrant gene expression program ochestrated by wild-type IRF4 for their survival. Here we show that an aggressive malignancy of mature B cells, the activated B cell for of Diffuse Large B Cell lymphoma (ABC-DLBC), also depends on IRF4 for survival. With genome-wide expression profiling and localization (ChIP-Seq) assays, we identified IRF4 target genes in ABC-DLBCL as members of diverse pathways related to B cell biology and malignant behavior, distinct from IRF4 targets in MM. For example, we find the gene encoding the NFkB signal transduction adapter protein CARD11 is a target of IRF4 activation, driving the critical NFkB pathway in ABC-DLBCL. Further, we find enrichment of DNA binding motifs for ETS-IRF factors in regions of IRF4 binding in ABC-DLBCL suggesting cooperative activity between IRF4 and an ETS family transcription factor. Through complementation assays we show that IRF4 and the critical ABC-DLBCL ETS factor SPIB interact with one another and are key to ABC-DLBCL survival. Together our data show that ABC-DLBCL is addicted to the interaction between IRF4 and SPIB, in part through a positive feedback loop invovling CARD11 and the activation of the NFkB pathway. These data suggest theraepeutic potential in targeting the IRF4:SPIB interface in ABC-DLBCL. Gene expression was analyzed using Agilent human 4X44K oligo gene expression arrays. Cell lines (HBL1, OCILY3, TMD8-ABC-DLBCL; KMS12-MM) were infected with control (shControl, Cy3) or shIRF4_3'UTR (Cy5) constructs, and changes in gene expression were monitored over time after induction of the shRNA with doxycyclin. For each of the three ABC-DLBCL cell line a four timepoint series (24, 48, 72, 96 hrs) of shRNA induction was analyzed, for a total of 12 arrays. In HBL-1 a second shRNA targeting the IRF4 cds (shIRF4_cds) was used in a similar time course of shRNA induction (4 arrays). For the KMS12 MM cell line a three point time course was analyzed using the shIRF4_3'UTR with one technical (using the same RNA sample) duplicate time point measurement (4 arrays). ChIP-Seq data not provided.
2011-07-01 | E-GEOD-22901 | biostudies-arrayexpress
Project description:High expression of the FOXP1 transcription factor distinguishes the highly aggressive Activated B Cell (ABC) type of Diffuse Large B Cell Lymphoma (DLBCL) from the more indolent Germinal Center (GCB) DLBCL subtype and is correlated with poor prognosis. A genetic or functional role for FOXP1 in lymphomagenesis and/or tumor maintenance, however, remains unknown. Here, we report that sustained expression of FOXP1 is necessary for ABC DLBCL cell line survival. Genome-wide transcript profiling reveals that FOXP1 acts directly and indirectly by enforcing expression of known ABC DLBCL hallmarks, including the classical NF-kappaB survival pathway. Our data further suggest that FOXP1 maintains the ABC subtype distinction by repressing gene expression programs dominant in GCB DLBCL and supports a model in which the target of ABC DLBCL transformation is a transitory cell type en route from the germinal center B cell to the terminally differentiated plasma cell.
2015-12-01 | GSE64586 | GEO
Project 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. The complete dataset is comprised of three experiments with the male HBL-1 ABC DLBCL cell line: a) 8 paired GEP measurements after NFKBIZ inhibition by shRNA, b) 6 paired GEP measurements after applying the MLN inhibitor and c) 4 two-color measurements after applying a MALT inhibitor. This dataset includes 4 two-color measurements of the male HBL-1 ABC DLBCL cell line after applying a MALT inhibitor.
2013-07-22 | E-GEOD-46973 | biostudies-arrayexpress
Project description:Chronic active B cell receptor (BCR) signaling, a hallmark of the ABC subtype of diffuse large B cell lymphoma (DLBCL), engages the CARD11-MALT1-BCL10 (CBM) adapter complex to activates IkappaB kinase (IKK) and the classical NF-kappaB pathway. Here we show that the CBM complex includes the E3 ubiquitin ligases cIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-kappaB activity in ABC DLBCL. cIAP1/2 attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation. SMAC mimetic drugs target cIAP1/2 for destruction, and consequently suppress NF-kappaB and selectively kill BCR-dependent ABC DLBCL lines, supporting their clinical evaluation in patients with ABC DLBCL. Samples from four ABC DLBCL cell lines (HBL1, TMD8, OCILY3, and OCILY10) were exposed to 2.5 uM birinapant for 2, 4, 6, and 24 hours (n=16). Samples from 2 ABC DLBCL cell lines (HBL1 and TMD8) were transduced with shRNA and induced with doxycycline for 3 and 4 days (n=4).
2016-09-01 | E-GEOD-73281 | biostudies-arrayexpress
Project description:To identify differentially expressed genes regulated by FOXP1 in DLBCL cells via gene expression profiling of GCB-DLBCL (DB, K422) and ABC-DLBCL (OCI-Ly3, HBL-1) cell lines treated with siRNA targeting FOXP1 or non-silencing siRNA control. Two GCB-DLBCL (DB, K422) and two ABC-DLBCL (OCI-Ly3, HBL-1) cell lines were each treated separately with two independent siRNA oligonucleotides targeting FOXP1 (siFOXP1_308, siFOXP1_309) or non-silencing siRNA (siCtrl). Biological replicates derived from three independent experiments were obtained, RNA-extracted and subsequently hybridized into a human microarray platform for gene expression profiling.
2015-10-27 | E-GEOD-71526 | biostudies-arrayexpress
Project description:The medicinal active phenothiazine mepazine acts as a small molecule inhibitor of the MALT1 protease. Mepazine selectively inhibits cleavage activity of recombinant and cellular MALT1 by a noncompetitive mechanism. MALT1 activity is required for NF-kappaB signaling and survival of aggressive lymphoma belonging to the ABC-DLBCL (activated B-cell-type of diffuse large B-cell lymphoma) entity. Gene expression profiling was carried out in the ABC-DLBCL cell line HBL1 after treatment with mepazine (20 microM) for 6, 12, and 24 hr. Mepazine inhibits anti-apoptotic NF-kB signaling and thereby survival of these cells.
2012-07-31 | GSE39741 | GEO
Project description:To identify differentially expressed genes regulated by FOXP1 in DLBCL cells via gene expression profiling of GCB-DLBCL (DB, K422) and ABC-DLBCL (OCI-Ly3, HBL-1) cell lines treated with siRNA targeting FOXP1 or non-silencing siRNA control.
2015-10-27 | GSE71526 | GEO
Project description:The medicinal active phenothiazine mepazine acts as a small molecule inhibitor of the MALT1 protease. Mepazine selectively inhibits cleavage activity of recombinant and cellular MALT1 by a noncompetitive mechanism. MALT1 activity is required for NF-kappaB signaling and survival of aggressive lymphoma belonging to the ABC-DLBCL (activated B-cell-type of diffuse large B-cell lymphoma) entity. Gene expression profiling was carried out in the ABC-DLBCL cell line HBL1 after treatment with mepazine (20 microM) for 6, 12, and 24 hr. Mepazine inhibits anti-apoptotic NF-kB signaling and thereby survival of these cells. Using Agilent 2-color gene expression microarrays (GPL10332) mepazine-treated HBL1 cells were compared with DMSO in the control channels.
2012-07-31 | E-GEOD-39741 | biostudies-arrayexpress