Academic Journal
Resistance to vincristine in DLBCL by disruption of p53-induced cell cycle arrest and apoptosis mediated by KIF18B and USP28
| العنوان: | Resistance to vincristine in DLBCL by disruption of p53-induced cell cycle arrest and apoptosis mediated by KIF18B and USP28 |
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| المؤلفون: | Rovsing, Anne Bruun, Thomsen, Emil Aagaard, Nielsen, Ian, Skov, Thomas Wisbech, Luo, Yonglun, Dybkær, Karen, Mikkelsen, Jacob Giehm |
| المصدر: | Rovsing , A B , Thomsen , E A , Nielsen , I , Skov , T W , Luo , Y , Dybkær , K & Mikkelsen , J G 2023 , ' Resistance to vincristine in DLBCL by disruption of p53-induced cell cycle arrest and apoptosis mediated by KIF18B and USP28 ' , British Journal of Haematology , vol. 202 , no. 4 , pp. 825-839 . https://doi.org/10.1111/bjh.18872 |
| سنة النشر: | 2023 |
| المجموعة: | Aarhus University: Research |
| مصطلحات موضوعية: | cancer, CHOP, CRISPR/Cas9, drug resistance, lymphomas, p53, Cyclophosphamide/therapeutic use, Prednisone/therapeutic use, Humans, Tumor Suppressor Protein p53/genetics, Kinesins/genetics, Vincristine/pharmacology, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Cell Cycle Checkpoints, Lymphoma, Large B-Cell, Diffuse/drug therapy, Rituximab/therapeutic use, Doxorubicin/pharmacology, Ubiquitin Thiolesterase, Precision Medicine, Apoptosis |
| الوصف: | The frontline therapy R-CHOP for patients with diffuse large B-cell lymphoma (DLBCL) has remained unchanged for two decades despite numerous Phase III clinical trials investigating new alternatives. Multiple large studies have uncovered genetic subtypes of DLBCL enabling a targeted approach. To further pave the way for precision oncology, we perform genome-wide CRISPR screening to uncover the cellular response to one of the components of R-CHOP, vincristine, in the DLBCL cell line SU-DHL-5. We discover important pathways and subnetworks using gene-set enrichment analysis and protein–protein interaction networks and identify genes related to mitotic spindle organization that are essential during vincristine treatment. The inhibition of KIF18A, a mediator of chromosome alignment, using the small molecule inhibitor BTB-1 causes complete cell death in a synergistic manner when administered together with vincristine. We also identify the genes KIF18B and USP28 of which CRISPR/Cas9-directed knockout induces vincristine resistance across two DLBCL cell lines. Mechanistic studies show that lack of KIF18B or USP28 counteracts a vincristine-induced p53 response suggesting that resistance to vincristine has origin in the mitotic surveillance pathway (USP28-53BP1-p53). Collectively, our CRISPR screening data uncover potential drug targets and mechanisms behind vincristine resistance, which may support the development of future drug regimens. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| DOI: | 10.1111/bjh.18872 |
| الاتاحة: | https://pure.au.dk/portal/en/publications/12f05784-03dd-4b41-9f57-b4e941f246b9 https://doi.org/10.1111/bjh.18872 https://pure.au.dk/ws/files/408371723/Br_J_Haematol_-_2023_-_Rovsing_-_Resistance_to_vincristine_in_DLBCL_by_disruption_of_p53_induced_cell_cycle_arrest_and.pdf |
| Rights: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.83928BBC |
| قاعدة البيانات: | BASE |
| DOI: | 10.1111/bjh.18872 |
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