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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: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152069 | GEO | 2021/06/24

REPOSITORIES: GEO

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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: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.

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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]

2021-06-24 | GSE152028 | 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.

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

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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 [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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