Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML
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PROVIDER: PRJNA682420 | ENA |
REPOSITORIES: ENA
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Project description:We report that loss of EZH2 provides leukaemia cells with a selective growth advantage, which mediates chemotherapy resistance. This resistance is conferred by up regulation of direct and indirect EZH2 target genes.
2021-03-12 | GSE162623 | GEO
Project description: Not available
| S-EPMC7955088 | biostudies-literature
Project description:Chemotherapy resistance is the main impediment in the treatment of acute myeloid leukaemia (AML). Despite rapid advances, the various mechanisms that lead to resistance development remain to be defined in detail. Here we report that loss-of-function mutations (LOF) in the histone methyltransferase EZH2 have the potential to confer resistance against the chemotherapeutic agent cytarabine. We identify seven distinct EZH2 mutations leading to loss of H3K27 trimethylation via multiple mechanisms. Analysis of matched diagnosis and relapse samples reveal a heterogenous regulation of EZH2 and a loss of EZH2 in 50% of patients. We confirm that loss of EZH2 induces resistance against cytarabine in the cell lines HEK293T and K562 as well as in a patient-derived xenograft (PDX) model. Proteomics and transcriptomics analysis reveal that resistance is conferred by upregulation of multiple direct and indirect EZH2 target genes that are involved in apoptosis evasion, augmentation of proliferation and alteration of transmembrane transporter function. Our data indicates, that loss of EZH2 results in upregulation of its target genes, providing the cell with a selective growth advantage, which mediates chemotherapy resistance.
2021-03-12 | PXD023139 | Pride
Project description:The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B-cells and targeted by somatic mutations in B-cell lymphomas. Here we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions in mice. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B-cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets in B-cells, and in human B-cell lymphomas. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GCB-type DLBCLs are mostly addicted to EZH2, regardless of mutation status, but not the more differentiated ABC-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting. RNA sequencing and H3K27me3 ChIP sequencing of human DLBCL cell lines and murine BCL1 cell line. RNA sequencing, H3K27me3 and H3K4me3 ChIP sequencing of B cells from de-identified human tonsills.
2013-05-13 | E-GEOD-45982 | biostudies-arrayexpress
Project description:Epigenetic regulators are commonly mutated in cancer. Activating mutations and overexpression of the lysine histone methyltransferase EZH2 occur in lymphoma and other malignancies, while loss-of-function mutations are found in myeloid malignancies. We study this apparent contradiction, examining the importance of cellular context for Ezh2 loss during the evolution of a single malignancy, Acute Myeloid Leukemia (AML). Remarkably, we observe diametrically opposite functions for Ezh2 at early and late stages during the evolution of leukemias generated by different AML-associated fusion-oncogenes. During disease maintenance we demonstrate that Ezh2 functions as an oncogene that may be therapeutically targeted. In contrast, Ezh2 acts as a tumour suppressor during AML induction and loss-of-function EZH2 mutations occur early in AML patient samples and confer a poor prognosis. Integrated genomic analysis demonstrates that different expression programmes are de-repressed during AML induction and maintenance following Ezh2 loss. During disease induction, Ezh2 loss de-represses a subset of bivalent promoters that resolve towards gene activation, inducing a feto-oncogene programme including genes such as Plag1, whose overexpression phenocopies Ezh2 loss to accelerate AML induction in mouse models. Our data highlight the importance of cellular context and phase of disease evolution for Ezh2 function. Moreover, we further identify EZH2 as a potential target in AML, whilst providing reassurance of the safety of this therapeutic strategy.
2019-03-07 | GSE112724 | GEO
Project description:Patients with primary refractory acute myeloid leukemia (AML) have a dismal long-term prognosis. Elucidating the resistance mechanisms to induction chemotherapy could help identify strategies to improve AML patient outcomes. Herein, we retrospectively analyzed the multi-omics data of more than 1,500 AML cases and found that patients with spliceosome mutations had a higher risk of developing refractory disease. RNA splicing analysis revealed that the mis-spliced genes in refractory patients converged on translation-associated pathways, promoted mainly by U2AF1 mutations. Integrative analyses of binding and splicing in AML cell lines substantiated that the splicing perturbations of mRNA translation genes originated from both the loss and gain of mutant U2AF1 binding. In particular, the U2AF1-S34F and U2AF1-Q157R mutants orchestrated the inclusion of exon 11 (encoding a premature termination codon) in the eukaryotic translation initiation factor 4A2 (EIF4A2). This aberrant inclusion led to reduced eIF4A2 protein expression via nonsense-mediated mRNA decay. Consequently, U2AF1 mutations caused a net decrease in global mRNA translation that induced the integrated stress response (ISR) in AML cells, which was confirmed by single-cell RNA-seq. The induction of ISR enhanced the ability of AML cells to respond and adapt to stress, contributing to chemoresistance. A pharmacologic inhibitor of ISR, ISRIB, sensitized U2AF1 mutant cells to chemotherapy. These findings highlight a resistance mechanism by which U2AF1 mutations drive chemoresistance and provide a therapeutic approach for AML through targeting the ISR pathway.
2024-02-20 | GSE256127 | GEO
Project description:The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B-cells and targeted by somatic mutations in B-cell lymphomas. Here we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions in mice. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B-cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets in B-cells, and in human B-cell lymphomas. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GCB-type DLBCLs are mostly addicted to EZH2, regardless of mutation status, but not the more differentiated ABC-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting.
2013-05-13 | GSE45982 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE41651: Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer [expression] GSE41652: Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer [ChIP-seq] Refer to individual Series
2012-11-15 | E-GEOD-41653 | biostudies-arrayexpress
Project description:Poor outcome of AML patients is closely related with therapy failure or relapse after initial response. The underlying mechanisms remain largely unknown. In this study we discovered the histone methyltransferase EZH2 as a novel marker for response to chemotherapy and patients` survival. Protein levels of EZH2 and subsequently H3K27 trimethylation (H3K27me3) are reduced in chemoresistant AML cells. To analyze which genomic regions were affected by the loss of EZH2 and reduced H3K27me3 mark we performed Chromatin Immunoprecipitation followed by high-throughput DNA sequencing (ChIP-Seq). ChIP-Seq for the H3K27me3 repressive mark revealed genome-wide differences between sensitive (MV4-11) and resistant (MV4-11R) cells. Overall, 4699 genomic regions showed a more than 1.5 fold reduction of H3K27me3 around TSS ±5kb in MV4-11R compared to MV4-11cells. Promoter regions of HOX genes, classical targets of PRC2, revealed drastically reduced H3K27me3 enrichment in the MV4-11R cells. The H3K27me3 level at the transcriptional start site (TSS) of the ABCC1 promoter was decreased in resistant compared to sensitive cells (Fig. 6D) with increased levels of H3K4me3 and H3K27ac. As expected, we found H3K27me3 enrichments to be inversely correlated with gene expression whereas histone modifications H3K4me3 and H3K27ac, known as markers for active genes, positively correlated with gene expression in our analysis. Differentially regulated genes were characterized to be involved in protein modification/phosphorylation pathways and signaling and apoptosis.
2016-11-22 | GSE61785 | GEO
Project description:Although the majority of acute myeloid leukemia (AML) patients initially respond to chemotherapy, most of them subsequently relapse due to persistent, chemoresistant disease. However, the mechanistic basis by which AML cells persist during chemotherapy has not been fully delineated. Recurrent somatic mutations in the DNA methyltransferase 3A gene (DNMT3A), most frequently at arginine 882 (DNMT3Amut), are commonly observed in AML patients, and are also detected in elderly subjects with clonal hematopoiesis in the absence of leukemic transformation. DNMT3Amut AML patients have an inferior outcome when treated with standard dose daunorubicin-based induction chemotherapy, suggesting that DNMT3Amut AML cells can persist following chemotherapy and drive relapse. DNMT3Amut cells show impaired nucleosome eviction and chromatin remodeling in response to DNA damage in the setting of anthracycline exposure. This defect leads to an inability to sense and repair DNA damage, which results in the accumulation of single-stranded DNA breaks and increased mutagenesis. Our studies identify a critical role for DNMT3A R882 mutations in driving AML chemoresistance, and highlight the importance of chromatin remodeling in the response to cytotoxic chemotherapy.
2016-11-14 | GSE86827 | GEO