Identification of BLNK and BTK as mediators of rituximab-induced programmed cell death by CRISPR screens in GCB-subtype diffuse large B-cell lymphoma

Emil Aagaard Thomsen, Anne Bruun Rovsing, Mads Valdemar Anderson, Hanne Due, Jinrong Huang, Yonglun Luo, Karen Dybkær, Jacob Giehm Mikkelsen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

16 Citations (Scopus)
53 Downloads (Pure)

Abstract

Diffuse large B-cell lymphoma (DLBCL) is characterized by extensive genetic heterogeneity, and this results in unpredictable responses to the current treatment, R-CHOP, which consists of a cancer drug combination supplemented with the humanized CD20-targeting monoclonal antibody rituximab. Despite improvements in the patient response rate through rituximab addition to the treatment plan, up to 40% of DLBCL patients end in a relapsed or refractory state due to inherent or acquired resistance to the regimen. Here, we employ a lentiviral genome-wide clustered regularly interspaced short palindromic repeats library screening approach to identify genes involved in facilitating the rituximab response in cancerous B cells. Along with the CD20-encoding MS4A1 gene, we identify genes related to B-cell receptor (BCR) signaling as mediators of the intracellular signaling response to rituximab. More specifically, the B-cell linker protein (BLNK) and Bruton's tyrosine kinase (BTK) genes stand out as pivotal genes in facilitating direct rituximab-induced apoptosis through mechanisms that occur alongside complement-dependent cytotoxicity (CDC). Our findings demonstrate that rituximab triggers BCR signaling in a BLNK- and BTK-dependent manner and support the existing notion that intertwined CD20 and BCR signaling pathways in germinal center B-cell-like-subtype DLBCL lead to programmed cell death.

Original languageEnglish
JournalMolecular Oncology
Volume14
Issue number9
Pages (from-to)1978-1997
Number of pages20
ISSN1574-7891
DOIs
Publication statusPublished - 1 Sept 2020

Bibliographical note

© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Keywords

  • B-cell receptor
  • CD20
  • CRISPR
  • CRISPR library screen
  • lentiviral vectors
  • rituximab

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