Resistance to vincristine in DLBCL by disruption of p53-induced cell cycle arrest and apoptosis mediated by KIF18B and USP28

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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.

Original languageEnglish
JournalBritish Journal of Haematology
Pages (from-to)825-839
Number of pages15
Publication statusPublished - Aug 2023


  • 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


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