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Combined inhibition of EZH2 and degradation of Ikaros has synergistic effects in germinal center B-cell diffuse large B-cell lymphoma

ABSTRACT: Combined inhibition of EZH2 and degradation of Ikaros has synergistic effects in germinal center B-cell diffuse large B-cell lymphoma

PROVIDER: PRJNA638187 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11960153.fastq.gz	Fastqsanger.gz
	SRR11960154.fastq.gz	Fastqsanger.gz
	SRR11960155.fastq.gz	Fastqsanger.gz
	SRR11960156.fastq.gz	Fastqsanger.gz
	SRR11960157.fastq.gz	Fastqsanger.gz

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Combined inhibition of EZH2 and degradation of Ikaros has synergistic effects in germinal center B-cell diffuse large B-cell lymphoma [RNA-seq]

Project description:Combined inhibition of EZH2 and degradation of Ikaros has synergistic effects in germinal center B-cell diffuse large B-cell lymphoma [RNA-seq]

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Combined inhibition of EZH2 and degradation of Ikaros has synergistic effects in germinal center B-cell diffuse large B-cell lymphoma [ChIP-seq]

Project description:Combined inhibition of EZH2 and degradation of Ikaros has synergistic effects in germinal center B-cell diffuse large B-cell lymphoma [ChIP-seq]

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Combined inhibition of EZH2 and degradation of Ikaros has synergistic effects in germinal center B-cell diffuse large B-cell lymphoma [ChIP-seq]

Project description:To explore the therapeutic opportunities to enhance the clinical efficacy of EZH2 inhibitors in treating diffuse large B-cell lymphoma (DLBCL), a genome-wide drug sensitizing CRISPR/Cas9 screen was conducted in the presence of tazemetostat. We found that the loss of IKZF1 or IKZF3 augmented the potency of tazemetostat on DLBCL. Treating cells with lenalidomide, an immunomodulatory drug that degrades IKZF1 and IKZF3, in combination with tazemetostat, recapitulated the effects observed in the drug sensitizing screen. The combined drug treatment showed even higher synergistic effects, by triggering either cell cycle arrest or apoptosis, on a broader range of DLBCL cell lines, regardless of EZH2 mutation status. RNAseq analysis revealed strong upregulation of the interferon signaling and antiviral immune response signatures. Gene expression of key factors such as IRF7 and DDX58 were highly induced in cells treated with lenalidomide and tazemetostat, with a concomitant enrichment of H3K27 acetylation at their promoters as delineated in ChIPseq and ChIP qPCR analyses. Furthermore, transcriptome analysis and immunofluorescence staining demonstrated pronounced expression of a wide range of endogenous retroviruses (ERVs), with significant overlaps between the upregulated ERV loci and well-defined H3K27me3 enriched regions in EZH2-mutant lymphoma cell lines. Our data underscore the synergistic interplay between lenalidomide and tazemetostat on modulating epigenetic changes, resulting in upregulation of the interferon response and de-repression of ERVs, and ultimately to reduced growth of GCB-type DLBCL.

2021-06-24 | GSE152028 | GEO

Combined inhibition of EZH2 and degradation of Ikaros has synergistic effects in germinal center B-cell diffuse large B-cell lymphoma [RNA-seq]

2021-06-24 | GSE151607 | GEO

Targeting DOT1L and EZH2 synergizes in breaking the germinal center identity of Diffuse Large B Cell Lymphoma

Project description:Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factors MYC and BCL6, and the epigenetic writers DOT1L and EZH2. GCB-like Diffuse Large B Cell Lymphomas (GCB-DLBCLs) arise from GC B cells and closely resemble their cell of origin. Given the dependency of GC B cells on DOT1L and EZH2, we investigated the role of these epigenetic regulators in GCB-DLBCL cell lines and observed that GCB-DLBCLs synergistically depend on the combined activity of DOT1L and EZH2. Mechanistically, inhibiting both enzymes led to enhanced derepression of PRC2 target genes compared to EZH2 single treatment, along with the derepression of BCL6 target genes and suppression of MYC target genes. The sum of all these alterations results in a ‘cell identity crisis,’ wherein GCB-DLBCLs lose their pro-proliferative GC identity and partially undergo plasma cell differentiation, a state associated with poor survival. In support of this model, combined epi-drugging of DOT1L and EZH2 prohibited the outgrowth of human GCB-DLBCL xenografts in vivo. We conclude that the malignant behavior of GCB-DLBCLs strongly depends on DOT1L and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL.

2025-10-14 | PXD056212 | Pride

DNA methylation profiling in primary Diffuse Large B cell Lymphoma (DLBCL) and normal Germinal Center B Cells

Project description:Diffuse Large B-Cell Lymphoma (DLBCL) is the most common aggressive form of non-Hodgkin lymphoma with variable biology and clinical behavior. The current classification does not fully explain the biological and clinical heterogeneity of DLBCLs. In this study we carried out genome-wide DNA methylation profiling of 140 DLBCL samples and 10 normal germinal center B-cells (NGCBs) using the HELP assay and hybridization to a custom Roche NimbleGen promoter array. We defined methylation disruption as a main epigenetic event in DLBCLs and designed a method for measuring the methylation variability of individual cases. We then used a novel approach for unsupervised hierarchical clustering based on the extent of DNA methylation variability. This approach identified 6 clusters (A-F). The extent of methylation variability was associated with survival outcomes, with significant differences in overall and progression-free survival. The novel clusters are characterized by disruption of specific biological pathways like cytokine-mediated signaling, ephrin signaling and pathways associated with apoptosis and cell cycle regulation. In a subset of patients, we profiled gene expression and genomic variation to investigate their interplay with methylation changes. This study is the first to identify novel epigenetic clusters of DLBCLs and their aberrantly methylated genes, molecular associations and survival. DNA methylation profiling in 140 primary denovo Diffuse Large B cell Lymphoma (DLBCL) samples from patients that had undergone R-CHOP chemotherapy and 10 purified normal Germinal Center B Cells

2014-01-18 | E-GEOD-54200 | biostudies-arrayexpress

Tonic B-Cell-Receptor Signaling in the Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma

Project description:Multiple types of B-cell lymphoma respond clinically to BTK inhibition, reflecting their dependence on B-cell receptor signaling. The germinal center B-cell subtype of diffuse large B-cell lymphoma resists BTK inhibition, but we found that B-cell receptor elimination in cell lines of this lymphoma type reduced their size and proliferation. Their B-cell receptor signals in a “tonic”, antigen-independent manner, requiring SYK, CD19, and phosphorylation of a specific tyrosine residue in the CD79A immunoreceptor tyrosine-based activation motif domain. The effect of B-cell receptor elimination or inhibition in these lines is proportional to their B-cell receptor surface density and its relative contribution to AKT activity, on which these lines uniformly depend, and is rescued by spontaneous or induced loss of PTEN protein. Biomarker-guided targeting of tonic B-cell receptor signaling may improve treatment of germinal center B-cell lymphoma.

2017-01-01 | GSE80615 | GEO

Microarray expression profile of long noncoding RNAs in germinal center-like diffuse large B-cell lymphoma cell lines.

Project description:The contributions of long noncoding RNAs (lncRNAs) to the development of germinal center (GCB)-like diffuse large B-cell lymphoma (DLBCL) remain largely unknown. The aim of this study was to investigate the expression profile of lncRNAs in human GCB DLBCL cell lines (OCI-ly1 and OCI-ly19) and normal B lymphocytes by microarray. We demonstrated that 21,539 lncRNAs were expressed in all samples analyzed, of which 1,648 lncRNAs were upregulated and 2,671 lncRNAs were downregulated in GCB DLBCL cell lines (OCI-ly1 and OCI-ly19) (≥2.0-fold, P<0.05).

2019-01-01 | GSE97336 | GEO

Proteome profiling of mouse germinal center B cells

Project description:Productive B cell responses are critical to protect a host from infection. The spleen and lymph nodes are populated by resting follicular B cells, which can enter germinal centers upon antigen encounter. Once in the germinal center, B cells migrate between the dark and light zones, where they undergo somatic hypermutation and selection, respectively. While germinal center B cells have been studied, an intense molecular understanding of these cells/subsets (and the differences between them) is lacking.

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Combined inhibition of EZH2 and degradation of Ikaros has synergistic effects in germinal center B-cell diffuse large B-cell lymphoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-06-24 | GSE152069 | GEO