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Gene expression changes between sensitive and YK-4-279-resistant Ewing's Sarcoma cell lines

ABSTRACT: Microarray gene expression analysis conducted from cell lines in each of three cohorts: (1) Resistant ES cell lines, (2) Sensitive parental ES cell lines treated with YK-4-279 for 72 hours, and (3) untreated sensitive parental ES cell lines (Three replicates from TC32 & TC71 original parental cell lines) We used microarrays to detail the global programme of gene expression underlying mechanism of resistance to YK-4-279 within parental sensitive and resistant selected Ewing's Sarcoma cell lines. We identified distinct classes of up-regulated genes during this process. Total RNA was extracted from the cell lines using the Qiagen miRNeasy Mini kit. RNA quality was assessed to have an RNA integrity number before amplification and labeling using AffymetrixM-bM-^@M-^Ys GeneChip GeneChipM-BM-.3M-bM-^@M-^Y IVT Express Kit following manufacturerM-bM-^@M-^Ys instructions. Amplified and biotinylated cRNAs were hybridized onto Affymetrix GeneChip Human Genome U133A 2.0 cartridge arrays, Washed, and Stained with kit following manufacturerM-bM-^@M-^Ys instructions. Arrays were scanned using Affymetrix GeneChip Scanner 3000 and the initial raw data were extracted using Affymetrix GeneChip Command Console-Expression software. The statistical analyses of scanned data were performed using default setting on GeneSpring GX 12.1 software (Agilent).

ORGANISM(S): Homo sapiens

SUBMITTER: Joseph Ludwig

PROVIDER: E-GEOD-61042 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene expression changes between sensitive and YK-4-279-resistant Ewing's Sarcoma cell lines

Project description:Microarray gene expression analysis conducted from cell lines in each of three cohorts: (1) Resistant ES cell lines, (2) Sensitive parental ES cell lines treated with YK-4-279 for 72 hours, and (3) untreated sensitive parental ES cell lines (Three replicates from TC32 & TC71 original parental cell lines) We used microarrays to detail the global programme of gene expression underlying mechanism of resistance to YK-4-279 within parental sensitive and resistant selected Ewing's Sarcoma cell lines. We identified distinct classes of up-regulated genes during this process.

2014-09-04 | GSE61042 | GEO

Inhibition of the oncogenic fusion protein EWS-FLI1 causes G2/M cell cycle arrest and enhanced vincristine sensitivity in Ewing sarcoma

Project description:A chimeric fusion between the RNA binding protein EWS and the ETS family transcription factor FLI1 (EWS-FLI1), created from a chromosomal translocation, is implicated in driving the majority of Ewing sarcomas (ES) by modulation of transcription and alternative splicing. The small molecule YK-4-279 inhibits EWS-FLI1 function and induces apoptosis. We tested 69 anti-cancer drugs in combination with YK-4-279 and found that vinca alkaloids exhibited synergy with YK-4-279 in five ES cell lines. The combination of YK-4-279 and vincristine reduced tumor burden and increased survival in mice bearing ES xenografts. We determined that independent drug-induced events converged to cause this synergistic therapeutic effect. YK-4-279 rapidly induced G2/M arrest, increased the abundance of cyclin B1, and decreased EWS-FLI1–mediated expression of microtubule-associated proteins, which rendered cells more susceptible to microtubule depolymerization by vincristine. YK-4-279 reduced the expression of the EWS-FLI1 target gene encoding ubiquitin ligase UBE2C, and this in part contributed to the increase in cyclin B1. Biochemical assays revealed that YK-4-279 also increased the abundance of proapoptotic isoforms of MCL1 and BCL2, presumably through inhibition of alternative splicing by EWS-FLI1, thus promoting cell death in response to vincristine. Thus a combination of vincristine and YK-4-279 might be therapeutically effective in ES patients.

2017-09-14 | GSE103837 | GEO

RNA sequencing profiles of B progenitor cells derived from mouse ES cell, Yolk sac, fetal liver, and adult bone marrow.

Project description:We induced mouse embryonic stem cells (ESCs) into B progenitors in in vitro culture. We previously reported that B cells derived from extra-embryonic yolks sac (YS) belong to innate-like B-1 cells, not conventional B-2 cells. Since ES cell differentiation into Blood lineage, it recapitulates YS hematopoiesis, we hypothesized that B cells produced by mouse ESCs belong to B-1 cells as well. We transplanted ESC-derived B-progenitor cells into immunodeficient mice and confirmed that ES-derived B cells differentiate into only B-1 and marginal zone B cells, not B-2 cells in vivo. We preformed gene expression profiles by RNA sequencing comparing ESC-derived, YS-derived, fetal liver derived, and adult bone marrow derived B progenitor cells to see their characteristics.

2019-01-31 | GSE123809 | GEO

Homo sapiens

Project description:Gene expression changes between sensitive and YK-4-279-resistant Ewing's Sarcoma cell lines

| PRJNA260133 | ENA

Characterization of Ewing sarcoma resistance to the EWS-FLI1 inhibitor YK-4-279

Project description:Ewing sarcoma (ES) is the second most common pediatric malignancy of the bones and soft tissue, but few advances in therapeutic options have been made over the past several decades. A characteristic feature of ES that and an attractive therapeutic targets is the EWS-FLI1 fusion protein. A small molecule inhibitor of EWS-FLI1, YK-4-279 was as a targeted therapy option for Ewing sarcoma patients. A YK-4-279 analog, TK216, is currently in clinical trial. With any targeted therapy, there is always the risk that tumors will become resistant and stop responding to treatment. Here, we investigated resistance mechanisms to YK-4-279 (YK) by developing ES cell lines specifically resistant to YK. We found that expression of the cell surface protein CD99 was elevated in YK-resistant cells. Increased CD99 expression occurs within five days of YK treatment in vivo. When CD99 expression is reduced by shRNA, resistant cells regain sensitivity to YK but reducing CD99 expression in non-resistant cells does not affect sensitivity. Little is known about CD99 function in the context of Ewing sarcoma, but the data presented here indicates the function of CD99 is altered upon acquisition of YK resistance, and that CD99 serves a critical function in developed resistance to YK-4-279. RNA sequencing analysis yielded candidate genes that may also be involved in the YK resistance mechanism. We identified a potential modulator of CD99 function, ANO1, a member of the ANO family and a participant in membrane-bound ion channel activity. CD99 has previously been linked with membrane-associated ion channels. A functional association between the two proteins remains to be investigated.

2020-03-21 | GSE132762 | GEO

Donor dependent variations in hematopoietic differentiation among embryonic and induced pluripotent stem cell lines.

Project description:Hematopoiesis generated from human embryonic stem cells (ES) and induced pluripotent stem cells (iPS) are unprecedented resources for cell therapy. We compared hematopoietic differentiation potentials from ES and iPS cell lines originated from various donors and derived them using integrative and non-integrative vectors. Significant differences in differentiation toward hematopoietic lineage were observed among ES and iPS. The ability of engraftment of iPS or ES-derived cells in NOG mice varied among the lines with low levels of chimerism. iPS generated from ES cell-derived mesenchymal stem cells (MSC) reproduce a similar hematopoietic outcome compared to their parental ES cell line. We were not able to identify any specific hematopoietic transcription factors that allow to distinguish between good versus poor hematopoiesis in undifferentiated ES or iPS cell lines. However, microarray analysis showed genes differentially expressed in ES and iPS cell lines according to their hematopoietic potential. These results demonstrate the influence of genetic background in variation of hematopoietic potential rather than the reprogramming process.

2015-11-17 | GSE75051 | GEO

Transcript profiling of Candida albicans strain SC5314 treated with Ethylzingerone, Methylparaben or Triclosan

Project description:Determine the mode-of-action of Ethylzingerone (also named compound 279) using transcript profiling of C. albicans SC5314 strain exposed to different concentrations of Ethylzingerone.

2020-12-31 | E-MTAB-7908 | biostudies-arrayexpress

Hemogenic endothelial fate mapping reveals dual developmental origin of mast cells.

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2018-06-01 | GSE104790 | GEO

Gene Expression Analysis of Ara-C Resistance in AML

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