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Transcriptomic profiling of drug-naïve or proteasome inhibitor-resistant myeloma cell lines

ABSTRACT: RNA was extracted from myeloma cell lines that were either drug-naïve or resistant to bortezomib or carfilzomib and the transcriptome was characterised using RNA sequencing.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE144249 | GEO | 2021/12/01

REPOSITORIES: GEO

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Secondary proteasome inhibitor carfilzomib resistant myeloma cell lines

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Project description:RNA was extracted from myeloma cell lines which were made engraftable and resistant to bortezomib and the transcriptome was characterised using RNA sequencing.

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

Project 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.

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

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Tight Junction Protein 1 is a Modulator and Biomarker of Proteasome Inhibitor Sensitivity in Multiple Myeloma

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Transcriptomic profiling of drug-naïve or proteasome inhibitor-resistant myeloma cell lines

Project description:Transcriptomic profiling of drug-naïve or proteasome inhibitor-resistant myeloma cell lines

| PRJNA603122 | ENA

The mitochondrial protease LonP1 promotes proteasome inhibitor resistance in multiple myeloma.

Project description:Purpose: We report the NGS-derived transcriptome profiling (paired-end RNA-seq) following proteasome inhibition in the multiple myeloma cell line MM.1S. Methods: MM.1S cells were treated for six hours with the synthetic proteasome inhibitor lactacystin or clinically-approved proteasome inhibitor bortezomib and RNA expression changes were quantified and compared to DMSO control-treated cells by RNA-sequencing.

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Allosteric HSP70 inhibitors in Proteasome Inhibitor Resistant Multiple Myeloma

Project description:Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first mapped proteasome-associated genetic co-dependencies. We identified cytosolic heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma tumor cells overcoming PI-induced stress. These results led us to explore allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. We showed these compounds exhibit increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC mass spectrometry found that JGs have the most pronounced effect on the proteome not through inhibiting cytosolic HSP70s but instead through mitochondrial-localized HSP70, HSPA9/mortalin, destabilizing the 55S mitoribosome. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize myeloma proteostasis networks under therapeutic pressure while motivating further investigation of HSPA9 as a specific vulnerability in PI-resistant disease.

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