Identification of BLNK and BTK as mediators of rituximab-induced programmed cell death by CRISPR screens in GCB-subtype diffuse large B-cell lymphoma
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- Identification of BLNK and BTK as mediators of rituximab-induced programmed cell death by CRISPR screens in GCB-subtype diffuse large B-cell lymphoma
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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-encodingMS4A1gene, 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 language | English |
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Journal | Molecular Oncology |
Volume | 14 |
Issue number | 9 |
Pages (from-to) | 1978-1997 |
Number of pages | 20 |
ISSN | 1574-7891 |
DOIs | |
Publication status | Published - 2020 |
- B-cell receptor, CD20, CRISPR, CRISPR library screen, lentiviral vectors, rituximab, IMPAIR ANTITUMOR-ACTIVITY, CALCIUM INFLUX, TYROSINE PHOSPHORYLATION, INDUCED APOPTOSIS, ANTIGEN RECEPTOR, CD20 EXPRESSION, IN-VITRO, ANTIBODY, COMPLEMENT, GENE
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