ArticleMolecular cancer therapeutics2017
CRISPR Genome-Wide Screening Identifies Dependence on the Proteasome Subunit PSMC6 for Bortezomib Sensitivity in Multiple Myeloma.
Article in Molecular cancer therapeutics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 58 citations in OpenAlex.
- CRISPR application in hematological disorders: from bench to bedside.Blood advances · 2026Review
- Germline regulation of tumor evolutionary dynamics shapes multiple myeloma progression.bioRxiv : the preprint server for biology · 2026Article
- CRISPR/Cas9 screening identifies SUV39H2 as a key regulator of oHSV-1 resistance in oral squamous cell carcinoma.Cell death discovery · 2025Article
- Loss of correlated proteasomal subunit expression selectively promotes the 20SCommunications biology · 2025Article
- PSMC6 regulation of ovarian cancer cisplatin resistance unravels a new mode for proteasome targeting.International journal of biological sciences · 2025Article
- The mitochondrial pyruvate carrier complex potentiates the efficacy of proteasome inhibitors in multiple myeloma.Blood advances · 2023Article
- Applying CRISPR-Cas9 screens to dissect hematological malignancies.Blood advances · 2023Review
- Spatiotemporal assessment of immunogenomic heterogeneity in multiple myeloma.Blood advances · 2023Article
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- Article
- 19S Proteasome Subunits as Oncogenes and Prognostic Biomarkers in FLT3-Mutated Acute Myeloid Leukemia (AML).International journal of molecular sciences · 2022Article
- The molecular mechanism and challenge of targeting XPO1 in treatment of relapsed and refractory myeloma.Translational oncology · 2022Review
- Article
- Comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities.Haematologica · 2022Article
- Review
- Mutation landscape of multiple myeloma measurable residual disease: identification of targets for precision medicine.Blood advances · 2022Article
- Contribution of the Tumor Microenvironment to Metabolic Changes Triggering Resistance of Multiple Myeloma to Proteasome Inhibitors.Frontiers in oncology · 2022Review
- Single-cell transcriptomics of neuroblastoma identifies chemoresistance-associated genes and pathways.Computational and structural biotechnology journal · 2022Article
- Pan-cancer analysis identifies proteasome 26S subunit, ATPase (PSMC) family genes, and related signatures associated with prognosis, immune profile, and therapeutic response in lung adenocarcinoma.Frontiers in genetics · 2022Article
- Low expression of TCP1 (T-Complex 1) and PSMC1 (Proteasome 26S subunit, ATPase 1) in heterotopic ossification during ankylosing spondylitis.Bioengineered · 2021Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Bortezomib is highly effective in the treatment of multiple myeloma; however, emergent drug resistance is common. Consequently, we employed CRISPR targeting 19,052 human genes to identify unbiased targets that contribute to bortezomib resistance. Specifically, we engineered an RPMI8226 multiple myeloma cell line to express Cas9 infected by lentiviral vector CRISPR library and cultured derived cells in doses of bortezomib lethal to parental cells. Sequencing was performed on surviving cells to identify inactivated genes responsible for drug resistance. From two independent whole-genome screens, we selected 31 candidate genes and constructed a second CRISPR sgRNA library, specifically targeting each of these 31 genes with four sgRNAs. After secondary screening for bortezomib resistance, the top 20 "resistance" genes were selected for individual validation. Of these 20 targets, the proteasome regulatory subunit PSMC6 was the only gene validated to reproducibly confer bortezomib resistance. We confirmed that inhibition of chymotrypsin-like proteasome activity by bortezomib was significantly reduced in cells lacking PSMC6. We individually investigated other members of the PSMC group (PSMC1 to 5) and found that deficiency in each of those subunits also imparts bortezomib resistance. We found 36 mutations in 19S proteasome subunits out of 895 patients in the IA10 release of the CoMMpass study (https://themmrf.org). Our findings demonstrate that the PSMC6 subunit is the most prominent target required for bortezomib sensitivity in multiple myeloma cells and should be examined in drug-refractory populations.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.