Identification of BLNK and BTK as mediators of rituximab‐induced programmed cell death by CRISPR screens in GCB‐subtype diffuse large B‐cell lymphoma
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 i...
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Veröffentlicht in: | Molecular oncology 2020-09, Vol.14 (9), p.1978-1997 |
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Sprache: | eng |
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Zusammenfassung: | 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.
Genome‐wide clustered regularly interspaced short palindromic repeats‐based screening identify B‐cell receptor (BCR) signaling as a core mediator of rituximab sensitivity in OCI‐Ly‐7 cells, specifically through actions of the B‐cell linker protein and Bruton's tyrosine kinase proteins. This supports the notion of intertwined signaling pathways in germinal center B‐cell‐like‐subtype diffuse large B‐cell lymphoma involving stimulation of CD20 and BCR on the cellular path toward programmed cell death and reduction of CD20 levels. |
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ISSN: | 1574-7891 1878-0261 |
DOI: | 10.1002/1878-0261.12753 |