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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
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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.
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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 <<<
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Contributor(s) |
Martin B, Wheeler E, Tothova Z, Adelman K |
Citation(s) |
38170787 |
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Submission date |
Mar 12, 2022 |
Last update date |
Aug 01, 2024 |
Contact name |
Karen Adelman |
E-mail(s) |
karen_adelman@hms.harvard.edu
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Organization name |
Harvard Medical School
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Department |
Biological Chemistry and Molecular Pharmacology
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Street address |
45 Shattuck St. LHRRB-201a
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City |
Boston |
State/province |
MA |
ZIP/Postal code |
02115 |
Country |
USA |
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Platforms (1) |
GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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Samples (46)
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Relations |
BioProject |
PRJNA815671 |
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 Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |