Transcriptomic profiling of drug-naïve or proteasome inhibitor-resistant myeloma cell lines
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE144249 | GEO | 2021/12/01
REPOSITORIES: GEO
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Project description:Modulation of the activity of the ubiquitin-proteasome pathway with the proteasome inhibitor (PI) is an established component of therapy for plasma cell disorders. However, resistance emerges and the mechanism is incompletely understood. We generated carfilzomib-resistant (CR) myeloma cell lines by exposing drug-naive ANBL-6, KAS-6/1, U266, and OPM-2 cells to increasing concentrations of carfilzomib and then performed gene expression profiling (GEP) to identify prominent changes compared to their vehicle-treated counterparts, followed by exploration of the mechanism(s) of proteasome inhibitor resistance.
2016-10-09 | GSE62237 | GEO
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.
2023-12-10 | GSE235288 | GEO
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.
2020-02-18 | GSE124510 | GEO
Project description:This study provides a genome-wide map of changes in histone mark modifications and HDAC3 binding in response to protesome inhibition in the multiple myeloma cell line MM.1S. Chromatin immunoprecipitation assays were carried out to determine the genomic locations of histone modifications (H3K27ac, H3K4me1, H3K4me3) and histone deacetylase 3 (HDAC3) binding locations in multiple myeloma cells following proteasome inhibition with either lactacystin, bortezomib or carfilzomib. In addition, we report the effects of the overexpression of the E3-ubiquitin ligase Siah2 and the impact of HDAC3 knockdown on H3K27 acetylation levels in multiple myeloma cells treated with lactacystin. Our global ChIP-seq analysis of histone marks showed that enhancer and promoter marks (H3K4me1 and H3K4me3, respectively) present little response to proteasome inhibition, while the acetylation of histone H3K27 was significantly up- or down-regulated after three-hour treatment with proteasome inhibitors. Treatment of the cells with lactacystin, bortezomib or carfilzomib strongly increased HDAC3 recruitment at cell cycle and mitochondrial promoters, indicating that proteasome inhibition stabilized HDAC3 locally at the promoter of these genes to induce their repression. Furthermore, genome-wide ChIP-seq analysis of H3K27ac profiles showed that overexpression of Siah2 enhanced H3K27 acetylation levels at cell cycle and mitochondrial promoters.
2022-11-21 | GSE193301 | GEO
Project description:Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma. 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 vulnerability in 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.
2020-02-21 | PXD012172 | Pride
Project description:Proteasome inhibitors are important chemotherapeutics in the treatment of multiple myeloma, but they are currently used empirically as no markers of sensitivity have been validated. We have identified expression of tight junction protein (TJP) 1 as being associated with sensitivity of plasma cells in vitro and in vivo to proteasome inhibitors. TJP1 suppressed expression of genes in the major histocompatibility class II region, including two catalytically active immunoproteasome subunits, thereby decreasing proteasome activity, a critical determinant of proteasome inhibitor sensitivity. This occurred through suppression by TJP1 of signaling through the epidermal growth factor receptor/Janus kinase 1/signal transducer and activator of transcription 3 pathway. In the clinic, high TJP1 expression in myeloma patients was associated with a significantly higher likelihood of responding to bortezomib, and with a longer time-to-progression after treatment. Taken together, these data support the use of TJP1 as a biomarker of sensitivity and resistance to proteasome inhibitors. To further elucidate mechanisms of bortezomib resistance, we developed human-derived multiple myeloma cell lines with a 4-fold or greater resistance to bortezomib. Then total RNA for bortezomib resistant (BR) and wild type (WT) was extracted and used for comparison by gene expression profiling.
2015-12-31 | E-GEOD-52369 | biostudies-arrayexpress
Project description:Bortezomib (BTZ), Carfilzomib (CFZ) and Ixazomib (IXA) are proteasome inhibitors (PI) approved for Multiple Myeloma (MM) treatment. By design, they all target the rate-limiting proteasome beta 5 (B5) subunit. CFZ treatment increases the survival of patients with relapsed/refractory MM compared to BTZ but is associated with heart failure not commonly observed for BTZ. The molecular basis for CFZ-induced cardiotoxicity is poorly understood. We time to investigate the transcriptomic effects of acute proteasome inhibition in the murine heart.
2023-07-01 | E-MTAB-11028 | biostudies-arrayexpress
Project description:Proteasome inhibition constitutes a cornerstone of multiple myeloma (MM) treatment, with bortezomib, carfilzomib and ixazomib approved for clinical use. We observed a consistent and highly significant increase in the reticulocyte count during treatment with carfilzomib-based regimens in patients with relapsed MM, an observation not made in a matched cohort of bortezomib-treated patients. As this increased reticulocytosis was neither associated with elevated hemoglobin levels nor with hemolysis, we subsequently performed in vitro experiments to unravel the underlying mechanisms of this clinical observation. While carfilzomib did not affect erythroid differentiation of CD34+ hematopoietic progenitor cells, both continuous and pulse exposure to carfilzomib significantly impaired terminal maturation of purified primary reticulocytes towards erythrocytes. These results indicate that carfilzomib significantly impairs terminal erythroid maturation, independent of erythroid commitment, expansion or differentiation. Our results report the first pharmacologically induced delay in erythroid maturation as a mechanism for carfilzomib-induced reticulocytosis in MM patients. Quantitative proteomics using LC-MS/MS were performed to assess whether carfilzomib treatment alters the protein composition of reticulocytes
2020-02-20 | PXD014353 | Pride
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.
2022-05-27 | PXD032030 | Pride
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.
2021-03-06 | GSE166122 | GEO