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Genome-wide CRISPR-Cas9 knockout screening identifies NUDCD2 depletion as sensitizer for bortezomib, carfilzomib and ixazomib in multiple myeloma.

ABSTRACT: Genome-wide CRISPR-Cas9 knockout screening identifies NUDCD2 depletion as sensitizer for bortezomib, carfilzomib and ixazomib in multiple myeloma.

PROVIDER: PRJNA1285847 | ENA |

REPOSITORIES: ENA

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Genome-wide CRISPR-Cas9 knockout screening identifies NUDCD2 depletion as sensitizer for bortezomib, carfilzomib and ixazomib in multiple myeloma [CRISPR screen carfilzomib]

Project description:Genome-wide CRISPR-Cas9 knockout screening identifies NUDCD2 depletion as sensitizer for bortezomib, carfilzomib and ixazomib in multiple myeloma [CRISPR screen carfilzomib]

| PRJNA1287773 | ENA

Genome-wide CRISPR-Cas9 knockout screening identifies NUDCD2 depletion as sensitizer for bortezomib, carfilzomib and ixazomib in multiple myeloma [CRISPR screen bortezomib]

Project description:Genome-wide CRISPR-Cas9 knockout screening identifies NUDCD2 depletion as sensitizer for bortezomib, carfilzomib and ixazomib in multiple myeloma [CRISPR screen bortezomib]

| PRJNA1287776 | ENA

Genome-wide CRISPR-Cas9 knockout screening identifies NUDCD2 depletion as sensitizer for bortezomib, carfilzomib and ixazomib in multiple myeloma [CRISPR screen carfilzomib]

Project description:Background/Objectives: The treatment of multiple myeloma (MM) remains a challenge as almost all patients will eventually relapse. Proteasome inhibitors are a cornerstone in the management of MM. Unfortunately, validated biomarkers predict-ing drug response are largely missing. Therefore, we aimed to identify genes associated with drug resistance or sensitization to proteasome inhibitors. Methods: We per-formed genome-wide CRISPR-Cas9 knockout (KO) screens in human KMS-28-BM my-eloma cells to identify genetic determinants associated with resistance or sensitization to proteasome inhibitors. Results: We show that KO of KLF13 and PSMC4 induces drug resistance, while NUDCD2, OSER1 and HERC1 KO cause drug sensitization. Sub-sequently, we focused on top sensitization hit, NUDCD2, which acts as a co-chaperone of Hsp90 to regulate the LIS1/dynein complex. RNA sequencing showed downregula-tion of genes involved in the ERAD pathway and in ER-associated ubiqui-tin-dependent protein catabolic processes in both untreated and carfilzomib-treated NUDCD2 KO cells, suggesting that NUDCD2 depletion alters protein degradation. Furthermore, bortezomib-treated NUDCD2 KO cells showed a decreased expression of genes that have a function in oxidative phosphorylation and the mitochondrial mem-brane, such as Carnitine Palmitoyltransferase 1A (CPT1A). CPT1A catalyzes the up-take of long chain fatty acids into mitochondria. Mitochondrial lipid metabolism has recently been reported as a possible therapeutic target for MM drug sensitivity. Con-clusions: These results contribute to the search of therapeutic targets that can sensitize MM patients to proteasome inhibitors.

2025-07-16 | GSE301948 | GEO

Genome-wide CRISPR-Cas9 knockout screening identifies NUDCD2 depletion as sensitizer for bortezomib, carfilzomib and ixazomib in multiple myeloma.

2025-07-16 | GSE301632 | GEO

Genome-wide CRISPR-Cas9 knockout screening identifies NUDCD2 depletion as sensitizer for bortezomib, carfilzomib and ixazomib in multiple myeloma [CRISPR screen bortezomib]

2025-07-16 | GSE301947 | GEO

Carfilzomib-induced reticulocytosis in patients with multiple myeloma is caused by impaired terminal erythroid maturation

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

Single cell RNA sequencing of murine hearts after acute proteasome inhibition

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

Comparison of the gene expression profiles of carfilzomib-resistant derivatives versus parental human myeloma cell lines

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

Secondary proteasome inhibitor carfilzomib resistant myeloma cell lines

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

Comparative expression analysis of carfilzomib-resistant and parental LP-1 human multiple myeloma cells

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

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