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ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma

ABSTRACT: ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma

PROVIDER: PRJNA1032929 | ENA |

REPOSITORIES: ENA

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ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [RNA-seq]

Project description:Immunomodulatory Drugs (IMiDs) are a backbone therapy for multiple myeloma (MM). Despite their efficacy, most patients develop resistance and the mechanism(s) are not fully defined. Here, we show that IMiD responses are directed by IMiD-dependent degradation of IKZF1 and IKZF3 that bind to enhancers necessary to sustain the expression of MYC and other myeloma oncogenes. IMiD treatment universally depleted chromatin-bound IKZF1, but eviction of P300 and BRD4 co-activators only occurred in IMiD-sensitive cells. IKZF1-bound enhancers overlapped other transcription factor-binding motifs, including ETV4. ChIP-seq showed that ETV4 bound to the same enhancers as IKZF1, and ETV4 CRISPR/Cas9-mediated ablation resulted in sensitization of IMiD-resistant MM. ETV4 expression is associated with IMiD resistance in cell lines, poor prognosis in patients, and upregulated at relapse. These data indicate that ETV4 alleviates IKZF1 and IKZF3 dependency in MM by maintaining oncogenic enhancer activity and identify transcriptional plasticity as a previously unrecognized mechanism of IMiD resistance.

2023-10-30 | GSE246435 | GEO

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ChIP-seq]

2023-10-30 | GSE246429 | GEO

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ATAC-seq]

2023-10-30 | GSE246426 | GEO

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ChIP-seq]

Project description:ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ChIP-seq]

| PRJNA1032924 | ENA

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ATAC-seq]

Project description:ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [ATAC-seq]

| PRJNA1032919 | ENA

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [RNA-seq]

Project description:ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma [RNA-seq]

| PRJNA1032930 | ENA

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma

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

2023-10-29 | GSE246436 | GEO

Spatiotemporal lineage derepression by cell crowding-induced ETV4 inactivation

Project description:All extant amniotes employ a single-layered epithelium of epiblasts as a starting material for gastrulation, suggesting the necessity of the epithelial structure for three germ layer derivation. Using a human embryonic stem cell (hESC) epithelium as a model system, we found that local epithelial crowding derepresses the neuroectoderm fate by spatiotemporal inactivation of ETV4. ETV4 serves as a genetic toggle switch that links cell density to lineage fates. Mechanistically, cell crowding blocks FGF receptor endocytosis by reduced cell-extracellular matrix (ECM) interaction. Disrupted endocytosis decreases ETV4 protein stability by ERK inactivation. Mathematical modeling of epithelial crowding demonstrates that the cooperativity of integrin-ECM interaction transforms the gradient of crowdedness into bistable ETV4 transition, which ensures the switch-like function of ETV4 in lineage determination. Our results propose local cell crowding in a stem cell epithelium as a key cellular mechanism for spatiotemporal regulation of lineage fates.

2024-03-12 | GSE183702 | GEO

Murine ES Cells: Control vs. ETV4/5 double KO

Project description:ETS-related transcription factors ETV4 and ETV5 play crucial roles for organogenesis and morphogenesis. We compared the transcriptional profiles between wild-type and ETV4 and ETV5 double knockout (ETV4/5 dKO) ES cells by an oligo DNA microarray analysis. Self-renewal capacity and pluripotency are known to be controlled by an ES cell-specific transcription factor network; therefore, we focused on transcription-associated genes. Of 1258 transcription-related genes, 47 genes were significantly downregulated and 98 genes were significantly upregulated in ETV4/5 dKO ES cells. Several genes whose expression is specific to undifferentiated ES were repressed in ETV4/5 dKO ES cells. In contrast, expression of differentiation markers was enhanced in ETV4/5 dKO ES cells.

2015-09-13 | GSE47225 | GEO

ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via Î±-ketoglutarate

Project description:In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while Î±-ketoglutarate levels decrease under hypoxia in control cells, Î±-ketoglutarate is paradoxically increased by hypoxia when ACC1 or ACLY are depleted. Supplementation with Î±-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4 via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased Î±-ketoglutarate. These results reveal that ACC1/ACLY- Î±-ketoglutarate-ETV4 is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future. DESIGN: H1975 lung cancer cells transduced with a scramble shRNA hairpin or two different shRNAs against ACLY, ACC1, or ETV4 under hypoxia.

2015-12-10 | E-GEOD-61286 | biostudies-arrayexpress

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