The effect of c-Myc over-expression on the sensitivity to Tipifarnib treatment in three cancer cell lines
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE210029 | GEO | 2022/08/01
REPOSITORIES: GEO
Similar Datasets
Project description:The effect of c-Myc over-expression on the sensitivity to Tipifarnib treatment in three cancer cell lines
| PRJNA863472 | ENA
Project description:Currently there is no method available to predict response to farnesyltransferase inhibitors (FTI). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib, in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1:APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy. This two-gene ratio was validated by quantitative PCR (QPCR) in the newly diagnosed AML cohort. We further demonstrated that this classifier could predict response to tipifarnib in an independent set of 54 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days, p = 0.0001), which was shown to be independent of other prognostic factors including a previously described gene expression classifier predictive of overall survival. Therefore, these data indicate that a two-gene expression assay may have utility in categorizing a population of AML patients who are more likely to respond to tipifarnib. Experiment Overall Design: 34 samples from 34 patients
2008-06-17 | E-GEOD-8970 | biostudies-arrayexpress
Project description:Gene signatures were derived to separate responders from nonresponders by tipifarnib treatment. Keywords: response analysis
2007-01-31 | GSE5122 | GEO
Project description:Currently there is no method available to predict response to farnesyltransferase inhibitors (FTI). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib, in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1:APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy. This two-gene ratio was validated by quantitative PCR (QPCR) in the newly diagnosed AML cohort. We further demonstrated that this classifier could predict response to tipifarnib in an independent set of 54 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days, p = 0.0001), which was shown to be independent of other prognostic factors including a previously described gene expression classifier predictive of overall survival. Therefore, these data indicate that a two-gene expression assay may have utility in categorizing a population of AML patients who are more likely to respond to tipifarnib. Keywords: classification
2007-09-12 | GSE8970 | GEO
Project description:Gene signatures were derived to separate responders from nonresponders by tipifarnib treatment. Experiment Overall Design: 58 samples from 58 patients
2008-06-13 | E-GEOD-5122 | biostudies-arrayexpress
Project description:Oncogenic levels of Myc expression sensitize cells to multiple apoptotic stimuli and this protects long-lived organisms from cancer development. How cells discriminate physiological from supra-physiological levels of Myc is largely unknown. Here we show that induction of apoptosis by Myc in breast epithelial cells requires association of Myc with Miz1. Gene expression and ChIP-sequencing experiments show that oncogenic levels of Myc, but not of MycV394D, a point mutant that does not bind Miz1, recruit Miz1 to core promoters and enable binding of Myc/Miz1 complexes to low-affinity target sites, correlating with repression of a specific set of target genes. Repressed genes encode proteins involved in cell adhesion, migration and wound healing; their promoters are enriched for binding sites of the serum response (SRF) factor. Restoring SRF activity attenuates Myc-induced apoptosis in response to glutamine starvation, exposure to Trail and to DNA damage. We propose that supra-physiological levels of Myc engage Miz1 in repressive DNA binding complexes and suppress transcriptional progress. MIZ1, MYC-ER and MYC-ERVD ChIP-Seq with 10E2 and HC20 anti-ERalpha antibodies in MCF10A cells, performed on an Illumina IIx Genome Analyzer. Input sample is accessioned as GSM1423726.
2015-07-10 | E-GEOD-59146 | biostudies-arrayexpress
Project description:Oncogenic levels of Myc expression sensitize cells to multiple apoptotic stimuli and this protects long-lived organisms from cancer development. How cells discriminate physiological from supra-physiological levels of Myc is largely unknown. Here we show that induction of apoptosis by Myc in breast epithelial cells requires association of Myc with Miz1. Gene expression and ChIP-sequencing experiments show that oncogenic levels of Myc, but not of MycV394D, a point mutant that does not bind Miz1, recruit Miz1 to core promoters and enable binding of Myc/Miz1 complexes to low-affinity target sites, correlating with repression of a specific set of target genes. Repressed genes encode proteins involved in cell adhesion, migration and wound healing; their promoters are enriched for binding sites of the serum response (SRF) factor. Restoring SRF activity attenuates Myc-induced apoptosis in response to glutamine starvation, exposure to Trail and to DNA damage. We propose that supra-physiological levels of Myc engage Miz1 in repressive DNA binding complexes and suppress transcriptional progr 4 different experimental conditions were analyzed: MYC-ER 4-OHT treated versus MYC-ER ctr-treated (EtOH), MYC-ER V394D 4-OHT treated versus MYC-ER V394D ctr-treated; 3 biological replicates for every condition.
2015-07-10 | E-GEOD-59145 | biostudies-arrayexpress
Project description:Oncogenic levels of Myc expression sensitize cells to multiple apoptotic stimuli and this protects long-lived organisms from cancer development. How cells discriminate physiological from supra-physiological levels of Myc is largely unknown. Here we show that induction of apoptosis by Myc in breast epithelial cells requires association of Myc with Miz1. Gene expression and ChIP-sequencing experiments show that oncogenic levels of Myc, but not of MycV394D, a point mutant that does not bind Miz1, recruit Miz1 to core promoters and enable binding of Myc/Miz1 complexes to low-affinity target sites, correlating with repression of a specific set of target genes. Repressed genes encode proteins involved in cell adhesion, migration and wound healing; their promoters are enriched for binding sites of the serum response (SRF) factor. Restoring SRF activity attenuates Myc-induced apoptosis in response to glutamine starvation, exposure to Trail and to DNA damage. We propose that supra-physiological levels of Myc engage Miz1 in repressive DNA binding complexes and suppress transcriptional progress.
2015-07-10 | GSE59146 | GEO
Project description:Oncogenic levels of Myc expression sensitize cells to multiple apoptotic stimuli and this protects long-lived organisms from cancer development. How cells discriminate physiological from supra-physiological levels of Myc is largely unknown. Here we show that induction of apoptosis by Myc in breast epithelial cells requires association of Myc with Miz1. Gene expression and ChIP-sequencing experiments show that oncogenic levels of Myc, but not of MycV394D, a point mutant that does not bind Miz1, recruit Miz1 to core promoters and enable binding of Myc/Miz1 complexes to low-affinity target sites, correlating with repression of a specific set of target genes. Repressed genes encode proteins involved in cell adhesion, migration and wound healing; their promoters are enriched for binding sites of the serum response (SRF) factor. Restoring SRF activity attenuates Myc-induced apoptosis in response to glutamine starvation, exposure to Trail and to DNA damage. We propose that supra-physiological levels of Myc engage Miz1 in repressive DNA binding complexes and suppress transcriptional progr
2015-07-10 | GSE59145 | GEO
Project description:BACKGROUND: Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles (EVs) including small EVs, or exosomes and their molecular cargo are known to modulate cell to cell communication during multiple cardiac diseases. However, the role of systemic EV biogenesis inhibition in the models of HF is not well documented and remains unclear. METHODS: We investigated the role of circulating exosomes during cardiac dysfunction and remodeling in a mouse transverse aortic constriction (TAC) model of HF. Importantly, we investigate the efficacy of Tipifarnib (Tip), a recently identified exosome biogenesis inhibitor that targets the critical proteins (Rab27a, nSmase2 and Alix) involved in exosome biogenesis for this mouse model of HF. In this study, 10-week-old male mice underwent TAC surgery, were randomly assigned to groups with and without Tip treatment (10 mg/kg three times/week) and monitored for 8 weeks and a comprehensive assessment was conducted through performed echocardiographic, histological, and biochemical studies. RESULTS: TAC significantly elevated circulating plasma exosomes and markedly increased cardiac left ventricular (LV) dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, injection of plasma exosomes from TAC mice induced LV dysfunction and cardiomyocyte hypertrophy in uninjured mice without TAC. On the contrary, treatment of Tip in TAC mice reduced circulating exosomes to baseline and remarkably improved LV functions, hypertrophy, and fibrosis. Tip treatment also drastically altered the miRNA profile of circulating post-TAC exosomes, including miR331-5p which was highly downregulated both in TAC circulating exosomes and in TAC cardiac tissue. Mechanistically, miR331-5p is crucial for inhibiting fibroblast-to-myofibroblast transition by targeting HOXC8, a critical regulator of fibrosis. Tipifarnib treatment in TAC mice upregulated the expression of miR331-5p that acts as potent repressor for one of the fibrotic mechanisms mediated by HOXC8. CONCLUSIONS: Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling to HF.
2024-05-07 | GSE266185 | GEO