github link
Accession IconSRP174924

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

Organism Icon Homo sapiens
Sample Icon 36 Downloadable Samples
Technology Badge IconIllumina HiSeq 4000, Illumina HiSeq 2000

Submitter Supplied Information

Description
Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma (MM). We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerabilityin myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma. Overall design: We examine 1) gene expression of MM cells in response to PI and 2)alternative splicing in response to PI and comparator chemotherapeutic compound. We further investigate splice factor mechanism in MM cells, by examining alternative splicing in MM with overexpression of wild type and mutant splice factor, SRSF1
PubMed ID
Total Samples
43
Submitter’s Institution
No associated institution

Samples

Show of 0 Total Samples
Filter
Add/Remove
Accession Code
Title
Cell line
Subject
Compound
Time
Processing Information
Additional Metadata
No rows found
Loading...