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Series GSE103068 Query DataSets for GSE103068
Status Public on Feb 27, 2018
Title Synergistic activity of BET inhibitor BI 894999 with PLK inhibitor volasertib in AML in vitro and in vivo
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Interactions between a new potent Bromodomain and extraterminal domain (BET) inhibitor BI 894999 and the polo-like kinase (PLK) inhibitor volasertib were studied in acute myeloid leukemia cell lines in vitro and in vivo. We provide data for the distinct mechanisms of action of these two compounds with a potential utility in AML based on gene expression, cell cycle profile and modulation of PD biomarkers such as MYC and HEXIM1. In contrast to BI 894999, volasertib treatment neither affects MYC nor HEXIM1 expression, but augments and prolongs the decrease of MYC expression caused by BI 894999 treatment. In vitro combination of both compounds leads to a decrease in S-Phase and to increased apoptosis. In vitro scheduling experiments guided in vivo experiments in disseminated AML mouse models. Co-administration of BI 894999 and volasertib dramatically reduces tumor burden accompanied by long-term survival of tumor-bearing mice and eradication of AML cells in mouse bone marrow. Together, these preclinical findings provide evidence for the strong synergistic effect of BI 894999 and volasertib, warranting future clinical studies in patients with AML to investigate this paradigm.
Overall design MV-4-11B cells were treated with either BI 894999 (1 nM or 35 nM) or volasertib (20 nM) or the combination of both for 4h or 24h. Subsequently cells were harvested for total RNA isolation using TriZol (Ambion) and further purified using miRNAeasy columns (Qiagen). Approximately 500ng of total RNA were subjected to library preparation using the TruSeq RNA Library Prep Kit v2 with polyA selection as recommended by the manufacturer (Illumina) without generating stranded information. Library were multiplexed and sequenced on a HiSeq1500 using paired-end sequencing with 50 cycles each.
Web link
Contributor(s) Tontsch-Grunt U, Gerlach D, Savarese F, Schweifer N, Kaya O
Citation(s) 29454094
Submission date Aug 24, 2017
Last update date May 15, 2019
Contact name Daniel Gerlach
Organization name Boehringer Ingelheim RCV GmbH & Co KG
Department Global Computational Biology and Digital Sciences
Street address Dr.-Boehringer-Gasse 5-11
City Vienna
ZIP/Postal code 1121
Country Austria
Platforms (1)
GPL18460 Illumina HiSeq 1500 (Homo sapiens)
Samples (36)
GSM2753257 BI00894999_1nM_24h_rep1
GSM2753258 BI00894999_1nM_24h_rep2
GSM2753259 BI00894999_1nM_24h_rep3
BioProject PRJNA400080
SRA SRP116140

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Supplementary file Size Download File type/resource
GSE103068_BI00894999_1nM_Volasertib_20nM_vs_DMSO_24h_dge.tsv.gz 2.8 Mb (ftp)(http) TSV
GSE103068_BI00894999_1nM_Volasertib_20nM_vs_DMSO_4h_dge.tsv.gz 2.8 Mb (ftp)(http) TSV
GSE103068_BI00894999_1nM_vs_DMSO_24h_dge.tsv.gz 2.8 Mb (ftp)(http) TSV
GSE103068_BI00894999_1nM_vs_DMSO_4h_dge.tsv.gz 2.9 Mb (ftp)(http) TSV
GSE103068_BI00894999_35nM_Volasertib_20nM_vs_DMSO_24h_dge.tsv.gz 2.8 Mb (ftp)(http) TSV
GSE103068_BI00894999_35nM_Volasertib_20nM_vs_DMSO_4h_dge.tsv.gz 2.9 Mb (ftp)(http) TSV
GSE103068_BI00894999_35nM_vs_DMSO_24h_dge.tsv.gz 2.8 Mb (ftp)(http) TSV
GSE103068_BI00894999_35nM_vs_DMSO_4h_dge.tsv.gz 2.9 Mb (ftp)(http) TSV
GSE103068_Volasertib_20nM_vs_DMSO_24h_dge.tsv.gz 2.8 Mb (ftp)(http) TSV
GSE103068_Volasertib_20nM_vs_DMSO_4h_dge.tsv.gz 2.8 Mb (ftp)(http) TSV
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