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Knock-down of BCL6 expression in human Diffuse Large B-Cell Lymphoma cell lines

ABSTRACT: This dataset was used to benchmark the Virtual Inference of Protein-activity by Regulon Readout algorithm (VIPER). Despite recent advances in molecular profiling, proteome-wide assessment of protein activity in individual samples remains a highly elusive target. In stark contrast, protein activity quantitation is increasingly critical to the dissection of key regulatory processes and to the elucidation of biologically relevant mechanisms. Importantly, its value extends to the study of drug activity, as most small molecules inhibit activity of their cognate protein substrates without affecting the protein‚Äôs or associated mRNA‚Äôs abundance. VIPER leverages the increasingly accurate and context specific knowledge of regulatory networks. Specifically, it uses the expression of the transcriptional targets most directly regulated by a given protein in an individual sample as a reporter for the computational inference of its activity. BCL6 knock down experiments were performed in OCI-Ly7 and Pfeiffer GCB-DLBCL cell lines. Both cell lines were maintained in 10% FBS supplemented IMDM medium and transiently transfected with either a BCL6-specific or a non-target control siRNA oligo in triplicate. Total RNA was isolated 48h after transfection and gene expression was profiled on H-GU133plus2 Affymetrix gene chips.

ORGANISM(S): Homo sapiens

SUBMITTER: Mariano Alvarez

PROVIDER: E-GEOD-45838 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Knock-down of BCL6 expression in human Diffuse Large B-Cell Lymphoma cell lines

Project description:This dataset was used to benchmark the Virtual Inference of Protein-activity by Regulon Readout algorithm (VIPER). Despite recent advances in molecular profiling, proteome-wide assessment of protein activity in individual samples remains a highly elusive target. In stark contrast, protein activity quantitation is increasingly critical to the dissection of key regulatory processes and to the elucidation of biologically relevant mechanisms. Importantly, its value extends to the study of drug activity, as most small molecules inhibit activity of their cognate protein substrates without affecting the protein’s or associated mRNA’s abundance. VIPER leverages the increasingly accurate and context specific knowledge of regulatory networks. Specifically, it uses the expression of the transcriptional targets most directly regulated by a given protein in an individual sample as a reporter for the computational inference of its activity.

2013-09-01 | GSE45838 | GEO

Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation

Project description:The transcriptional repressors BCL6 and BACH2 are crucial regulators of germinal center (GC) B-cell fate, and are known to interact and repress transcription of PRDM1, a key driver of plasma cell differentiation. How these factors cooperate is not fully understood. Herein we show that while GC formation is only minimally impaired in Bcl6+/- or Bach2+/- mice, double heterozygous Bcl6+/-Bach2+/- mice exhibit profound reduction in GC formation. Splenic B-cells from Bcl6+/- Bach2+/- mice display accelerated plasmacytic differentiation and high expression of key plasma cell genes such as Prdm1, Xbp1 and CD138. ChIP-seq revealed that in B-cells BACH2 is mostly bound to genes together with its heterodimer partner MAFK. The BACH2-MAFK complex binds to sets of genes known to be involved in the GC response, 60% of which are also targets of BCL6. Approximately 30% of BACH2 peaks overlap with BCL6 including cis-regulatory sequences of the PRDM1 gene. BCL6 also modulates BACH2 protein stability and their protein levels are positively correlated in GC B-cells. Therefore, BCL6 and BACH2 cooperate to orchestrate gene expression patterning in GC B cells through both transcriptional and biochemical mechanisms, which collectively determine the proper initiation and timing of terminal differentiation. ChIP-seq using P18 antibodies in OCI-Ly7 cells

2013-11-17 | E-GEOD-47784 | biostudies-arrayexpress

Chronic active pre-B cell receptor signaling drives BCL6 expression and represents a therapeutic target in a distinct subtype of acute lymphoblastic leukemia

Project description:BCL6fl/fl mouse bone marrow pre-B cells were transduced with an TCF3-PBX1 vector. The TCF3-PBX1 transduced BCL6fl/fl pre-B cells were then transduced with an empty vector (EV), or a Cre vector for Cre-mediated BCL6 deletion. Effect of BCL6 deletion in the TCF3-PBX1 pre-B cells were studied by Affymetrix GeneChip Mouse Genome 430 2.0 Arrays. TCF3-PBX1 transduced BCL6fl/fl mice bone marrow pre-B cells were tranduced with an empty vector (EV) or a Cre vector for BCL6 deletion

2015-02-08 | E-GEOD-59332 | biostudies-arrayexpress

BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint.

Project description:The B cell-specific BACH2 transcription factor is required for affinity maturation of mature B cells. Here, we show that Bach2 mediates negative selection at the pre-B cell receptor checkpoint and functions as a critical safeguard against leukemogenesis. Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments, and thus lack pre-B cell receptor expression. Upon productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends negative selection through BCL6-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, Bach2-mediated checkpoint control is frequently compromised and low levels of Bach2 expression represent a strong independent predictor of poor clinical outcome. Bach2+/+ pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53. Upon transformation with Myc, Bach2-/- pre-B cells fail to upregulate p53, form large colonies and initiate fatal leukemia in transplant recipient mice. ChIP-seq and gene expression analyses revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and multiple other checkpoint control genes. These findings identify Bach2 as a key activator of p53 in pre-B cells, which is critical to maintain stringency of the pre-B cell receptor checkpoint and an important barrier against leukemic transformation. ChIP-seq using BACH2 and BCL6 antibodies in OCI-Ly7 cells

2013-06-27 | E-GEOD-44420 | biostudies-arrayexpress

Gene expression profiling of two DLBCL cell lines upon shRNA mediated knockdown of EZH2

Project description:We studied transcriptional changes by Affymetrix human microarrays in 2 DLBCL cell lines as a result of shRNA mediated knockdown of EZH2. In eukaryotes, epigenetic post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and is responsible for repressing target gene expression through methylation of histone H3 on lysine 27 (H3K27). Over-expression of EZH2 is implicated in tumorigenesis and correlates with poor prognosis in multiple tumor types. Recent reports have identified somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The Y641 residue is the most frequently mutated residue, with 22% of GCB (Germinal Cell B-cell) DLBCL and FL harboring mutations at this site. These lymphomas exhibit increased H3K27 tri-methylation (H3K27me3) due to altered substrate preferences of the mutant enzymes. However, it is unknown whether direct inhibition of EZH2 methyltransferase activity alone will be effective in treating lymphomas carrying activating EZH2 mutations. Herein, we demonstrate that GSK126, a potent, highly-selective, SAM-competitive, small molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and dramatically inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma. Pfeiffer and KARPAS-422 cells were treated with either shRNA targeting EZH2 (shEZH2) or a non targeting control (shNTC) for 10 days.

2012-10-12 | E-GEOD-41239 | biostudies-arrayexpress

PRMT5 Interacts with the BCL6 Oncoprotein and is Required for Germinal Center Formation and Lymphoma Cell Survival

Project description:We have found that PRMT5 methylates BCL6 and is needed for its full transcriptional repressor activity. Concomitant inhibition of both BCL6 and PRMT5 exhibits synergistic killing of BCL6-expressing lymphoma cells.

2018-12-06 | GSE116963 | GEO

Borrowing Transcriptional Kinases to Activate Apoptosis [ChIP-seq]

Project description:Protein kinases are disease drivers whose therapeutic targeting traditionally centers on inhibition of enzymatic activity. Here chemically induced proximity is leveraged to convert kinase inhibitors into context-specific activators of therapeutic genes. Bivalent molecules that link ligands of the transcription factor B-cell lymphoma 6 (BCL6) to ATP-competitive inhibitors of cyclin-dependent kinases (CDKs) are developed to re-localize CDK to BCL6-bound loci on chromatin and direct phosphorylation of Pol II. The resulting BCL6-target proapoptotic gene expression translates into killing of diffuse large B-cell lymphoma (DLBCL) cells at 72h with EC50s of 0.9 – 10nM and specific ablation of the BCL6-dependent germinal center response in mice. The molecules exhibit 10,000-fold lower cytotoxicity in normal lymphocytes and are well tolerated in mice. Genomic and proteomic evidence corroborate a gain-of-function mechanism where, instead of global enzyme inhibition, a fraction of total kinase activity is borrowed and re-localized to BCL6-bound loci. The strategy demonstrates how kinase inhibitors can be used to context-specifically activate transcription, accessing new therapeutic space.

2024-09-18 | GSE245598 | GEO

Borrowing Transcriptional Kinases to Activate Apoptosis [RNA-seq]

2024-09-18 | GSE245599 | GEO

MLL4 (KMT2D) inactivating mutations lead to focal loss of H3K4me1/2 and deregulated gene expression in B cell lymphomas

Project description:We identified KMT2D target loci in OCI-LY7 by ChIPseq. KMT2D ChIPseq was carried out in the LY7 cell line (n=1).

2015-08-28 | E-GEOD-67314 | biostudies-arrayexpress

BCL6 repression of EP300 provides a basis for rational combinatorial therapy in diffuse large B cell lymphomas.

Project description:The BCL6 transcriptional repressor is a critical oncogene in diffuse large B-cell lymphomas (DLBCL). The specific BCL6 inhibitor RI-BPI potently kills DLBCL cells. We find that RI-BPI induces a particular gene expression signature in DLBCL. In order to identify classes of drugs that might synergize with RIBPI we examined the connectivity of this signature and found a strong association with HDAC and Hsp90 inhibitors. This was explained by the discovery that BCL6 directly represses the p300 lysine acetyltransferase and its co-factor BAT3. RI-BPI induced expression of p300 and BAT3, and p300 acetyltransferase activity, resulting in acetylation of p300 targets like p53 and Hsp90. As a consequence, RI-BPI could attenuate Hsp90 chaperone function, similar to the effect of Hsp90 and HDAC inhibitors. Induction of p300 and BAT3 was required for the anti-lymphoma effects of RI-BPI since specific blockade of either protein rescued DLBCL cells from the BCL6 inhibitor. RI-BPI synergistically killed DLBCL cells in combination with HDAC inhibitors (SAHA, TSA and VPA) and Hsp90 inhibitors (17-DMAG and PUH71). The combination of RI-BPI and SAHA, or RI-BPI and PU-H71 potently suppressed or even eradicated human DLBCL in mice. BCL6 repression of EP300 thus provides a basis for rational targeted combinatorial therapy for patients with DLBCL. Direct comparison of gene expression levels in DLBCL cell lines after 24hs of treatment with either a Bcl6 inhibitor peptide or control peptide

2010-09-21 | E-GEOD-24236 | biostudies-arrayexpress

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