RNA-seq analysis of the effects of BCL6-inhibiting and BCL6-degrading compounds in lymphoma cell lines
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE94099 | GEO | 2017/09/17
SECONDARY ACCESSION(S): PRJNA368848
REPOSITORIES: GEO
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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
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphomas worldwide and is characterized by a high diversity of genetic and molecular alterations. Chromosomal translocations and mutations leading to deregulated expression of the transcriptional repressor BCL6 occur in a significant fraction of DLBCL patients. An oncogenic role of BCL6 in the initiation of DLBCL has been shown as the constitutive expression of BCL6 in mice recapitulates the pathogenesis of human DLBCL. However, the role of BCL6 in tumor maintenance remains poorly investigated due to the absence of suitable genetic models and limitations of pharmacological inhibitors. Here, we have utilized tetracycline-inducible CRISPR/Cas9 mutagenesis to study the consequences of BCL6 deletion in established DLBCL models in culture and in vivo. We show that BCL6 knock-out in SU-DHL-4 cells in vitro results in an anti-proliferative response 4-7 days after Cas9 induction that was characterized by cell cycle (G1) arrest. Conditional BCL6 deletion in established DLBCL tumors in vivo induced a significant tumor growth inhibition with initial tumor stasis followed by slow tumor growth kinetics. Our findings support a role of BCL6 in the maintenance of lymphoma growth and showcase the utility of inducible CRISPR/Cas9 systems for probing oncogene addiction.
2020-03-23 | GSE127266 | GEO
Project description:BCL6 is a key oncogene in lymphoma pathogenesis. The expression of BCL6 in lymphoid cells can be deregulated by several mechanisms, including chromosomal translocations, somatic mutations in the promoter regulatory regions or reduced proteasome-mediated degradation. FBXO11 was recently identified as a major ubiquitin ligase involved in the degradation of BCL6 and is frequently inactivated in diffuse large B-cell lymphoma (DLBCL). In this work, we found that FBXO11 is frequently mutated in Burkitt lymphoma (BL) but rarely mutated in other BCL6-positive lymphomas, such as follicular lymphoma (FL). All mutations tested impaired FBXO11 mediated BCL6 degradation and FBXO11 knock-out completely stabilized BCL6 levels in human BL cell lines. Conditional deletion of one copy or both copies of FBXO11 in c-Myc-driven B cell lymphoma in mice accelerated lymphomagenesis, genetically confirming that FBXO11 is a haplo-insufficient oncosuppressor in lymphoma. In both FBOX11 WT and deficient BL mouse and human cell lines, blockade of BCL6 via a specific degrader or BCL6 inhibitors, impaired lymphoma growth in vitro and in vivo, an effect further enhanced by co-inhibition of c-Myc activity. Overall these findings not only establish FBXO11 as one of the most frequently mutated genes in BL, but also elucidate its biological functions in lymphomagenesis and thereby identify BCL6 as a specific therapeutic target in BL.
2021-12-31 | GSE159303 | GEO
Project description:Here, we find that the B cell lymphoma 6 (BCL6) repressor is enriched upon feeding and converges genome-wide with PPARs to opposingly control lipid metabolism.
2019-04-16 | GSE118787 | GEO
Project description:Here, we find that the B cell lymphoma 6 (BCL6) repressor is enriched upon feeding and converges genome-wide with PPARs to opposingly control lipid metabolism.
2019-04-16 | GSE118788 | GEO
Project description:Here, we find that the B cell lymphoma 6 (BCL6) repressor is enriched upon feeding and converges genome-wide with PPARs to opposingly control lipid metabolism.
2019-04-17 | GSE129920 | GEO
Project description:BCL6 is a transcription repressor that plays a crucial role in germinal center formation and lymphomagenesis. However, its role in myeloid malignancies remains unclear. Here, we explored the role of BCL6 in acute myeloid leukemia (AML). Heterogeneous levels of BCL6 were found across AML cell lines and primary AML samples. Cells with higher levels of BCL6 were indeed sensitive to treatment with BCL6 inhibitors. Gene expression profiling of AML cells treated with BCL6 inhibitor revealed a subset of target genes that are common with lymphoma cells. Ex vivo treatment of primary AML cells with BCL6 peptide inhibitor (BPI) induced apoptosis and decrease colony forming capacity which correlated with the levels of BCL6 expression . Importantly, inhibition of BCL6 in primary AML cells with either BPI or BCL6 siRNA resulted in significant reduction of leukemia initiating capacity using immunodeficient mice, suggesting ablation of leukemia stem cells (LSC). Such anti-LSC activity was also observed as downregulation of LSC gene signatures using gene expression analyses of cells treated with a BCL6 inhibitor. Importantly, treatment with cytarabine (AraC) induced BCL6 expression, and the levels of BCL6 induction were correlated with resistance to AraC. Treatment of AML primary derived xenografts (PDX) revealed that when AraC was combined with BCL6 inhibitor, inhibition of BCL6 significantly potentiated the efficacy of AraC and improved cytotoxic effects by interfering with the leukemia initiating capacity of AML cells. This suggests that pharmacological inhibition of BCL6 might provide a novel therapeutic strategy for ablation of LSCs and overcome chemoresistance in AML.
2020-08-01 | GSE133112 | GEO
Project description:In order to determine BCL6 target genes an EBV negative Burkitt's lymphoma cell line, DG75, was stably transfected with a tetracycline transactivator and tight doxycycline responsive expression of GFP was established. The endogenous BCL6 genes of this cell line were disrupted by homologous recombination and a BCL6 cDNA downstream of tetracycline responsive elements (TRE) was inserted to produce Bcl6-/-:tetBCL6-HA cells. Westerns demonstrated doxycycline dependent BCL6 expression.Bcl6-/-:tet. BCL6-HA cells (clone AB7) were either grown without doxycycline (control) or with 1 ug/ml doxycycline for 16, 48 or 96 hours. Total RNA was extracted using RNeasy minipreps (Qiagen) and concentration and quality were checked on the NanoDrop® ND- 1000 spectrophotometer (NanoDrop Technologies, USA) and the RNA Nano 6000 kit (Agilent Technologies) on a 2100 Bioanalyzer (Agilent Technologies). One hundred ng of total RNA was processed with the GeneChip® Eukaryotic Whole Transcript Sense Target Labelling Assay kit (Affymetrix) according to the manufacturer's details. Hybridisation and scanning of GeneChips® was carried out at the CSC/IC Microarray Centre, MRC Clinical Sciences Centre Imperial College London and data analysis by Bioinformatics Support Service, Imperial College London. Briefly, pre- processing of data was performed using GeneSpring GX 10.0.2 software (Agilent Technologies) which applied the "Exon RMA16"¸ algorhithm to the data set. Exon RMA16 performs background correction, quantile normalisation, median polish summarisation and variance stabilisation of 16. In background correction, intensity values of each individual array are corrected for non-specific binding by subtracting the average signal intensity of the area between spots from each probe set. Normalisation is required so multiple chips can be compared to each other. Quantile normalisation adjusts the distribution of probe intensity of each array analysed and so that the distribution of probe intensities for each array in a set of arrays is the same. Probe summarisation refers to the conversion of probe level values (there are approximately 26 probes per gene on each GeneChip®) to a single probe set expression value. Variance stabilisation of 16 refers to the addition of the value 16 to the expression values. By increasing the expression value, the variance of the data set is reduced and the distribution (defined by its mean and its variance) is stabilised.
2014-08-22 | GSE55301 | GEO
Project description:The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through de novo formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. Herein we show that the actions EZH2 in driving GC formation and lymphoma precursor lesions are dependent on the presence of the BCL6 transcriptional repressor, both of which are in turn dependent on the presence of non-canonical PRC1-BCOR complex. BCL6-BCOR complexes assemble preferentially at bivalent promoters in an H3K27me3-dependent manner. We observe specific induction of the CBX8 chromodomain protein in GC B cells. CBX8 binds to H3K27me3 at bivalent promoters and is required for stable association of BCOR complex and its histone modifications. CBX8 loss of function in B cells phenocopies loss of EZH2 and H3K27me3. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in vitro, in vivo and in primary human DLBCLs. KDM2B ChIP-sequencing of OCI-Ly1 cells
2016-07-20 | E-GEOD-81623 | biostudies-arrayexpress
Project description:Rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) for BCL6 in untreated and irradiated glioblastoma cell lines and a positive control lymphoma cell line.
| MSV000090288 | MassIVE