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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Standard

Identification of BLNK and BTK as mediators of rituximab-induced programmed cell death by CRISPR screens in GCB-subtype diffuse large B-cell lymphoma. / Thomsen, Emil Aagaard; Rovsing, Anne Bruun; Anderson, Mads Valdemar; Due, Hanne; Huang, Jinrong; Luo, Yonglun; Dybkaer, Karen; Mikkelsen, Jacob Giehm.

I: Molecular Oncology, Bind 14, Nr. 9, 2020, s. 1978-1997.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Harvard

APA

CBE

MLA

Vancouver

Author

Bibtex

@article{95588e0bac404faea0efc3f279283640,
title = "Identification of BLNK and BTK as mediators of rituximab-induced programmed cell death by CRISPR screens in GCB-subtype diffuse large B-cell lymphoma",
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 CRISPR 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 GCB-subtype DLBCL lead to programmed cell death.",
keywords = "B-cell receptor, CD20, CRISPR, CRISPR library screen, lentiviral vectors, rituximab",
author = "Thomsen, {Emil Aagaard} and Rovsing, {Anne Bruun} and Anderson, {Mads Valdemar} and Hanne Due and Jinrong Huang and Yonglun Luo and Karen Dybkaer and Mikkelsen, {Jacob Giehm}",
note = "This article is protected by copyright. All rights reserved.",
year = "2020",
doi = "10.1002/1878-0261.12753",
language = "English",
volume = "14",
pages = "1978--1997",
journal = "Molecular Oncology",
issn = "1574-7891",
publisher = "Elsevier BV",
number = "9",

}

RIS

TY - JOUR

T1 - Identification of BLNK and BTK as mediators of rituximab-induced programmed cell death by CRISPR screens in GCB-subtype diffuse large B-cell lymphoma

AU - Thomsen, Emil Aagaard

AU - Rovsing, Anne Bruun

AU - Anderson, Mads Valdemar

AU - Due, Hanne

AU - Huang, Jinrong

AU - Luo, Yonglun

AU - Dybkaer, Karen

AU - Mikkelsen, Jacob Giehm

N1 - This article is protected by copyright. All rights reserved.

PY - 2020

Y1 - 2020

N2 - 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 CRISPR 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 GCB-subtype DLBCL lead to programmed cell death.

AB - 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 CRISPR 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 GCB-subtype DLBCL lead to programmed cell death.

KW - B-cell receptor

KW - CD20

KW - CRISPR

KW - CRISPR library screen

KW - lentiviral vectors

KW - rituximab

UR - http://www.scopus.com/inward/record.url?scp=85088088682&partnerID=8YFLogxK

U2 - 10.1002/1878-0261.12753

DO - 10.1002/1878-0261.12753

M3 - Journal article

C2 - 32585766

VL - 14

SP - 1978

EP - 1997

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 9

ER -