NCBI Logo
GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
          Go
Series GSE198518 Query DataSets for GSE198518
Status Public on Jun 30, 2023
Title Splicing modulators impair DNA damage response and induce killing of cohesin-mutant MDS/AML
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary Splicing modulation is a promising treatment strategy pursued to date only in splicing-factor mutant cancers; however, its therapeutic potential is poorly understood outside of this context. Like splicing factors, genes encoding components of the cohesin complex are frequently mutated in cancer and are associated with poor outcomes in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, we show that cohesin mutations are biomarkers of sensitivity to drugs targeting splicing-factor SF3B1 (H3B-8800 and E-7107) and identify drug-induced alterations in splicing of DNA repair genes as the mechanism underlying this sensitivity. We demonstrate that treatment of cohesin-mutant cells with SF3B1 modulators results in impaired DNA damage response, accumulation of DNA damage, and increased sensitivity to a panel of chemotherapeutic agents in vitro and in vivo. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS/AML.
 
Overall design RNA-seq in wildtype or cohesin-mutant cells with or without treatment of splicing modulators. For all experiments at least two replicates were generated for each condition.

>>> Raw data not provided due to patient privacy concerns: PDX and patient RNA-seq samples <<<
 
Contributor(s) Martin B, Wheeler E, Tothova Z, Adelman K
Citation(s) 38170787
Submission date Mar 12, 2022
Last update date Aug 01, 2024
Contact name Karen Adelman
E-mail(s) karen_adelman@hms.harvard.edu
Organization name Harvard Medical School
Department Biological Chemistry and Molecular Pharmacology
Street address 45 Shattuck St. LHRRB-201a
City Boston
State/province MA
ZIP/Postal code 02115
Country USA
 
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (46)
GSM5949851 U937_WT-1_DMSO
GSM5949852 U937_WT-2_DMSO
GSM5949853 U937_WT-3_DMSO
Relations
BioProject PRJNA815671

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE198518_Cohesin_WT_AML_PDX_RNAseq_raw_gene_counts.txt.gz 382.5 Kb (ftp)(http) TXT
GSE198518_PDX_RNAseq_raw_gene_counts.tsv.gz 483.4 Kb (ftp)(http) TSV
GSE198518_PDX_rMATS_b1_Vehicle_b2_merged_E7107.tar.gz 48.4 Mb (ftp)(http) TAR
GSE198518_Patient_peripheal_blood_RNAseq_raw_gene_counts.txt.gz 452.3 Kb (ftp)(http) TXT
GSE198518_RAW.tar 28.0 Gb (http)(custom) TAR (of BW)
GSE198518_RNAseq_depth_normalized_gene_counts.txt.gz 858.0 Kb (ftp)(http) TXT
GSE198518_rMATS_Cohesin_WT_AML_PDX_b1_Vehicle_b2_E7107.tar.gz 39.9 Mb (ftp)(http) TAR
GSE198518_rMATS_patient1_7mg_4hr_H3B_vs_patient_Ra_Ly_preDose.tar.gz 11.2 Mb (ftp)(http) TAR
GSE198518_rMATS_patient2_20mg_4hr_H3B_vs_patient_Ma_Ar_preDose.tar.gz 17.1 Mb (ftp)(http) TAR
GSE198518_rMATS_patient3_10mg_2hr_H3B_vs_patient_Si_Cl_preDose.tar.gz 20.6 Mb (ftp)(http) TAR
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap