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Drug addiction unveils a repressive methylation ceiling in EZH2-mutant lymphoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199889 | GEO | 2023/02/08

REPOSITORIES: GEO

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Drug addiction unveils a repressive methylation ceiling in EZH2-mutant lymphoma.

Project description:Drug addiction, a phenomenon where cancer cells paradoxically depend on continuous drug treatment for survival, has uncovered cell signaling mechanisms and cancer codependencies. Here we discover mutations that confer drug addiction to inhibitors of the transcriptional repressor polycomb repressive complex 2 (PRC2) in diffuse large B-cell lymphoma. Drug addiction is mediated by hypermorphic mutations in the CXC domain of the catalytic subunit EZH2, which maintain H3K27me3 levels even in the presence of PRC2 inhibitors. Discontinuation of inhibitor treatment leads to overspreading of H3K27me3, surpassing a repressive methylation ceiling compatible with lymphoma cell survival. Exploiting this vulnerability, we show that inhibition of SETD2 similarly induces the spread of H3K27me3 and blocks lymphoma growth. Collectively, our findings demonstrate that constraints on chromatin landscapes can yield biphasic dependencies in epigenetic signaling in cancer cells. More broadly, we highlight how approaches to identify drug addiction mutations can be leveraged to discover cancer vulnerabilities.

| S-EPMC10522050 | biostudies-literature

Drug addiction unveils a repressive methylation ceiling in EZH2-mutant lymphoma

Project description:Drug addiction unveils a repressive methylation ceiling in EZH2-mutant lymphoma

| PRJNA821887 | ENA

EZH2 inhibitor efficacy in non-Hodgkin lymphoma does not require suppression of H3K27 mono-methylation

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-04-13 | E-GEOD-62058 | biostudies-arrayexpress

EZH2 variants differentially regulate polycomb repressive complex 2 in histone methylation and cell differentiation.

Project description:BACKGROUND:Polycomb repressive complex 2 (PRC2) is responsible for establishing and maintaining histone H3K27 methylation during cell differentiation and proliferation. H3K27 can be mono-, di-, or trimethylated, resulting in differential gene regulation. However, it remains unknown how PRC2 specifies the degree and biological effects of H3K27 methylation within a given cellular context. One way to determine PRC2 specificity may be through alternative splicing of Ezh2, PRC2's catalytic subunit, during cell differentiation and tissue maturation. RESULTS:We fully characterized the alternative splicing of Ezh2 in somatic cells and male germ cells and found that Ezh's exon 14 was differentially regulated during mitosis and meiosis. The Ezh2 isoform containing exon 14 (ex14-Ezh2) is upregulated during cell cycle progression, consistent with a role in maintaining H3K27 methylation during chromatin replication. In contrast, the isoform lacking exon 14 (ex14D-Ezh2) was almost exclusively present in spermatocytes when new H3K27me2 is established during meiotic differentiation. Moreover, Ezh2's transcript is normally controlled by E2F transcription activators, but in spermatocytes, Ezh2's transcription is controlled by the meiotic regulator MYBL1. Compared to ex14-EZH2, ex14D-EZH2 has a diminished efficiency for catalyzing H3K27me3 and promotes embryonic stem cell differentiation. CONCLUSIONS:Ezh2's expression is regulated at transcriptional and post-transcriptional levels in a cellular context-dependent manner. EZH2 variants determine functional specificity of PRC2 in histone methylation during cell proliferation and differentiation.

| S-EPMC6282306 | biostudies-literature

EZH2 inhibitor efficacy in non-Hodgkin lymphoma does not require suppression of H3K27 mono-methylation

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

2015-04-13 | GSE62058 | GEO

EZH2 Inhibition as a Therapeutic Strategy for Lymphoma with EZH2 Activating Mutations

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

2012-10-12 | GSE40972 | GEO

Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response.

Project description:Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells.

| S-EPMC7298875 | biostudies-literature

Lipid addiction via Fatty Acid Synthase activates PI3K signaling in B cell non-Hodgkin’s Lymphoma (bNHL)

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

2018-02-01 | GSE102765 | GEO

EZH2 suppresses the interferon-stimulated gene response in non-Hodgkin Lymphoma

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

2023-01-06 | GSE70703 | GEO

LATS2 regulates repressive epigenetic integrity via regulation of Polycomb repressive complex 2

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-07-25 | E-GEOD-63538 | biostudies-arrayexpress