Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Epigenetic regulation of NK cell-mediated immune response in multiple myeloma [RNA-Seq]

ABSTRACT: Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we performed two in vitro genome-wide CRISPR screens to systematically discover the regulators of sensitivity to Dara-mediated antibody-dependent cellular cytotoxicity (ADCC) and identified KDM6A. The loss of KDM6A led to a marked downregulation in CD38 expression by increasing H3K27me3 on the CD38 promoter, resulting in resistance to Dara-mediated ADCC. Yet, adding back CD38 did not completely rescue this phenotype. In fact, KDM6A loss also downregulated CD48, which promoted Dara resistance by inhibiting natural killer cell activity. Lowering the H3K27me3 with an EZH2 inhibitor restored sensitivity to Dara through CD38 and CD48 upregulation. These findings suggest KDM6A loss as a mechanism of Dara resistance and explore the strategy of using an EZH2 inhibitor, one of which is already FDA-approved, to improve the response to Dara in MM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228769 | GEO | 2024/01/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Epigenetic regulation of NK cell-mediated immune response in multiple myeloma [CRISPR screening 2]

Project description:Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we performed two in vitro genome-wide CRISPR screens to systematically discover the regulators of sensitivity to Dara-mediated antibody-dependent cellular cytotoxicity (ADCC) and identified KDM6A. The loss of KDM6A led to a marked downregulation in CD38 expression by increasing H3K27me3 on the CD38 promoter, resulting in resistance to Dara-mediated ADCC. Yet, adding back CD38 did not completely rescue this phenotype. In fact, KDM6A loss also downregulated CD48, which promoted Dara resistance by inhibiting natural killer cell activity. Lowering the H3K27me3 with an EZH2 inhibitor restored sensitivity to Dara through CD38 and CD48 upregulation. These findings suggest KDM6A loss as a mechanism of Dara resistance and explore the strategy of using an EZH2 inhibitor, one of which is already FDA-approved, to improve the response to Dara in MM.

2024-01-23 | GSE228770 | GEO

Epigenetic regulation of NK cell-mediated immune response in multiple myeloma [ChIP-Seq]

2024-01-23 | GSE228768 | GEO

Epigenetic regulation of NK cell-mediated immune response in multiple myeloma [CRISPR screening 1]

2024-01-23 | GSE228767 | GEO

Epigenetic regulation of NK cell-mediated immune response in multiple myeloma [ATAC-Seq]

2024-01-23 | GSE228766 | GEO

Transcriptomic analysis of natural killer (NK) cells after co-culture with RPMI 8226 multiple myleoma cell line in the presence or absence of peripheral blood lymphocytes

Project description:Isatuximab is an IgG1 antibody that recognizes CD38 molecule on the surface of MM plasma cells and induces, among others, NK cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC). In this study we sough to unveil the effect of anti-CD38 antibody on NK cells We used microarrays to detail the global programme of gene expression underlying the differences among NK cells co-cultured with RPMI 8226 cells in the presence or absence of anti-CD38 antibody

2021-11-02 | GSE122169 | GEO

Dissecting and Targeting Noncanonical Functions of EZH2 in Multiple Myeloma via an EZH2 Degrader [RNA-seq]

Project description:Multiple myeloma (MM) is the second most common hematological malignancy with poor prognosis. Enhancer of zeste homolog 2 (EZH2) is the enzymatic subunit of polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) for transcriptional repression. EZH2 have been implicated in numerous hematological malignancies, including MM. However, noncanonical functions of EZH2 in MM tumorigenesis are not well understood. Here, we uncovered a noncanonical function of EZH2 in MM malignancy. In addition to the PRC2-mediated and H3K27me3-dependent canonical function, EZH2 interacts with cMyc and co-localizes with gene activation markers, promoting MM tumorigenesis in a PRC2- and H3K27me3-independent manner. Both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes can be effectively depleted in MM cells by MS177, an EZH2 degrader we reported previously, leading to profound activation of EZH2-PRC2-associated genes and suppression of EZH2-cMyc oncogenic nodes. The MS177-induced degradation of both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes also reactivated immune response genes in MM cells. Phenotypically, targeting of EZH2’s both canonical and noncanonical functions by MS177 effectively suppressed the proliferation of MM cells both in vitro and in vivo. Collectively, this study uncovers a new noncanonical function of EZH2 in MM tumorigenesis and provides a novel therapeutic strategy, pharmacological degradation of EZH2, for treating EZH2-dependent MM.

2023-01-25 | GSE214668 | GEO

Dissecting and Targeting Noncanonical Functions of EZH2 in Multiple Myeloma via an EZH2 Degrader [CUT&RUN]

2023-01-25 | GSE214667 | GEO

Affinify Purification of EZH2 and phosphodeficient EZH2 identifies phosphorylation dependent interactions of EZH2

Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.

2018-07-03 | PXD010073 | Pride

Full proteome analysis of WT and Ezh2-KO K562 cells

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

HRP2-MINA complex reprograms t(4;14) multiple myeloma epigenome to dictate chemosensitivity to proteasome inhibitors [RNA-Seq]

Project description:Depletion of HRP2 induced remarkable resistance to PIs induced apoptosis of MM cells in vitro and in vivo, and suppressed expression of HRP2 was observed in bortezomib-resistant (BR) MM cells. Notably, HRP2 altered chemosensitivity more obviously in MM cells with t(4;14) translocation, and much remarkable resistant to PIs than other reagents. Moreover, HRP2 abolition of HRP2 augmented H3K27me3 modification, consequentially intensifying transcriptome alteration prone to cell survival and restriction of endoplasmic reticulum (ER) stress. Mechanistically, HRP2 recognized H3K36me2 and recruited the histone demethylases MYC-induced nuclear antigen (MINA) to degrade H3K27me3, released suppression on genes responsible for drug resistance, such as ATF3 and NR4A1. Thus, an EZH2 inhibitor, tazemetostat, synergistically sensitized anti-MM effect of bortezomib both in vitro and in vivo. Collectively, our study provides novel knowledge to understand the origination of chemoresistance in MM patients with t(4;14), and rationale for managing MM patients according to different genomic backgrounds.

2021-02-11 | GSE166524 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data