Whole Exome Sequencing Analysis of Carfilzomib-Related Cardiotoxicity in Multiple Myeloma Patients
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PROVIDER: PRJNA975678 | ENA |
REPOSITORIES: ENA
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Project description:Whole Exome Sequencing Analysis of Carfilzomib-Related Cardiotoxicity in Multiple Myeloma Patients
| PRJNA975677 | ENA
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: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:Carfilzomib Suppresses SENP1 to Trigger Cardiotoxicity by DDX17 Destabilization
| PRJNA1144389 | ENA
Project description:LP-1 cells were exposed to stepwise increasing concentrations of carfilzomib over a period of 18 weeks: cells adapted to growth in 4 nM carfilzomib by 4 weeks, in 6 nM in another 6 weeks and in 12 nM after a further 8 weeks. The resulting cell culture, denoted LP-1/Cfz, retained resistance to carfilzomib even when tested after removal of selective pressure for approximately 8 weeks.
2016-09-13 | GSE78069 | GEO
Project description:Carfilzomib has a good effect in treating multiple myeloma, but more and more clinical studies have shown that the drug can cause cardiac toxicity during use, but the mechanism of action is unclear. This study aimed to comprehensively elucidate the mechanism of CFZ-induced cardiomyopathy by constructing a C57BL/6 mouse model and combining cell experiments. The research results showed that the hearts of mice treated with CFZ appeared significantly enlarged, and the cardiac function indicators decreased. The serum enzyme LDH, AST, and CK-MB levels significantly increased, suggesting severe myocardial injury. RNA extraction and QPCR detection of the heart showed that the expression of heart hypertrophy and fibrosis markers increased. Meanwhile, histological staining found that there were fewer cardiomyocytes, damaged myofibrils, and cardiac fibrosis. In the cell experiments, CFZ treatment caused the release of more LDH from rat cardiomyocytes and H9C2 cells, increased CASPASE 3/7 activity, abnormal cell morphology, enlarged cell size, myocardial hypertrophy and fibrosis marker gene expression in cardiomyocytes. Through the study of the SUMOYLATION pathway, it was found that CFZ's effects on cardiomyocyte structure and function were related to the expression of SENP genes, especially SENP1, which showed a significant downregulation in cardiomyocytes and mouse heart tissue, and was positively correlated with the levels of cardiac injury marker genes. This study further explored the mechanism of action by specifically altering the expression of SENP1 in cardiomyocytes. The results show that the knockdown of SENP1 in cardiomyocytes leads to more severe myocardial damage after CFZ treatment, suggesting that the expression of SENP1 can potentially affect the cardiotoxicity caused by CFZ. Further, by using silver staining and mass spectrometry to identify the interacting proteins with SENP1 after CFZ treatment, we found that the knockdown of DDX17 had a similar myocardial injury effect as SENP1. Subsequently, through Co-IP, protein stability experiments, and ubiquitination analysis experiments, we determined that SENP1 can maintain the protein stability of DDX17 by inhibiting its SUMO modification, thereby preventing cardiomyocyte injury and apoptosis. We hope to provide a new perspective and potential cardioprotective strategy for clinical use.
2024-08-10 | GSE273971 | GEO
Project description:KMS-11 and KMS-34 cells were exposed to stepwise increasing concentrations of carfilzomib over a period of 18 weeks: cells adapted to growth in 4 nM carfilzomib by 4 weeks, in 6 nM in another 6 weeks and in 12 nM after a further 8 weeks. The resulting cell cultures, denoted KMS-11/Cfz and KMS-34/Cfz, respectively, retained resistance to carfilzomib even when tested after removal of selective pressure for approximately 8 weeks. KMS-11/Cfz and KMS-34/Cfz cells were profiled for gene expression after 1 week of growth in the absence of carfilzomib together with parental KMS-11 and KMS-34 cells which had not been selected in the drug (triplicate samples).
2015-07-09 | E-GEOD-69078 | biostudies-arrayexpress
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: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:CIDR: Whole Exome Sequencing of Multiple Myeloma
| PRJNA746364 | ENA