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A loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways. / de Rooij, Martin F. M.; Thus, Yvonne J.; Swier, Nathalie; Beijersbergen, Roderick L.; Pals, Steven T.; Spaargaren, Marcel.

In: Nature communications, Vol. 13, No. 1, 2136, 01.12.2022.

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@article{6da5b49894284641bf90f0266af31944,
title = "A loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways",
abstract = "The clinical introduction of the Bruton{\textquoteright}s tyrosine kinase (BTK) inhibitor ibrutinib, which targets B-cell antigen-receptor (BCR)-controlled integrin-mediated retention of malignant B cells in their growth-supportive lymphoid organ microenvironment, provided a major breakthrough in lymphoma and leukemia treatment. Unfortunately, a significant subset of patients is intrinsically resistant or acquires resistance against ibrutinib. Here, to discover novel therapeutic targets, we present an unbiased loss-of-adhesion CRISPR-Cas9 knockout screening method to identify proteins involved in BCR-controlled integrin-mediated adhesion. Illustrating the validity of our approach, several kinases with an established role in BCR-controlled adhesion, including BTK and PI3K, both targets for clinically applied inhibitors, are among the top hits of our screen. We anticipate that pharmacological inhibitors of the identified targets, e.g. PAK2 and PTK2B/PYK2, may have great clinical potential as therapy for lymphoma and leukemia patients. Furthermore, this screening platform is highly flexible and can be easily adapted to identify cell adhesion-regulatory proteins and signaling pathways for other stimuli, adhesion molecules, and cell types.",
author = "{de Rooij}, {Martin F. M.} and Thus, {Yvonne J.} and Nathalie Swier and Beijersbergen, {Roderick L.} and Pals, {Steven T.} and Marcel Spaargaren",
note = "Funding Information: The authors thank Cor Lieftink, Roel Kluin, and Jan Koster for bioinformatics hints & tips and Marjolein Lansbergen and Chayenne Veerman for generating some of the knockout cells. This work was supported by grants of Dutch Cancer Society (#7873, #10275), Lymph&Co, and the International Waldenstrom{\textquoteright}s Macroglobulinemia Foundation (IWMF)/Leukemia & Lymphoma Society (LLS) to M.S. and a grant of the Dutch Cancer Society (#12539) to R.L.B. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
day = "1",
doi = "10.1038/s41467-022-29835-y",
language = "English",
volume = "13",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

RIS

TY - JOUR

T1 - A loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways

AU - de Rooij, Martin F. M.

AU - Thus, Yvonne J.

AU - Swier, Nathalie

AU - Beijersbergen, Roderick L.

AU - Pals, Steven T.

AU - Spaargaren, Marcel

N1 - Funding Information: The authors thank Cor Lieftink, Roel Kluin, and Jan Koster for bioinformatics hints & tips and Marjolein Lansbergen and Chayenne Veerman for generating some of the knockout cells. This work was supported by grants of Dutch Cancer Society (#7873, #10275), Lymph&Co, and the International Waldenstrom’s Macroglobulinemia Foundation (IWMF)/Leukemia & Lymphoma Society (LLS) to M.S. and a grant of the Dutch Cancer Society (#12539) to R.L.B. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12/1

Y1 - 2022/12/1

N2 - The clinical introduction of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which targets B-cell antigen-receptor (BCR)-controlled integrin-mediated retention of malignant B cells in their growth-supportive lymphoid organ microenvironment, provided a major breakthrough in lymphoma and leukemia treatment. Unfortunately, a significant subset of patients is intrinsically resistant or acquires resistance against ibrutinib. Here, to discover novel therapeutic targets, we present an unbiased loss-of-adhesion CRISPR-Cas9 knockout screening method to identify proteins involved in BCR-controlled integrin-mediated adhesion. Illustrating the validity of our approach, several kinases with an established role in BCR-controlled adhesion, including BTK and PI3K, both targets for clinically applied inhibitors, are among the top hits of our screen. We anticipate that pharmacological inhibitors of the identified targets, e.g. PAK2 and PTK2B/PYK2, may have great clinical potential as therapy for lymphoma and leukemia patients. Furthermore, this screening platform is highly flexible and can be easily adapted to identify cell adhesion-regulatory proteins and signaling pathways for other stimuli, adhesion molecules, and cell types.

AB - The clinical introduction of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which targets B-cell antigen-receptor (BCR)-controlled integrin-mediated retention of malignant B cells in their growth-supportive lymphoid organ microenvironment, provided a major breakthrough in lymphoma and leukemia treatment. Unfortunately, a significant subset of patients is intrinsically resistant or acquires resistance against ibrutinib. Here, to discover novel therapeutic targets, we present an unbiased loss-of-adhesion CRISPR-Cas9 knockout screening method to identify proteins involved in BCR-controlled integrin-mediated adhesion. Illustrating the validity of our approach, several kinases with an established role in BCR-controlled adhesion, including BTK and PI3K, both targets for clinically applied inhibitors, are among the top hits of our screen. We anticipate that pharmacological inhibitors of the identified targets, e.g. PAK2 and PTK2B/PYK2, may have great clinical potential as therapy for lymphoma and leukemia patients. Furthermore, this screening platform is highly flexible and can be easily adapted to identify cell adhesion-regulatory proteins and signaling pathways for other stimuli, adhesion molecules, and cell types.

UR - http://www.scopus.com/inward/record.url?scp=85128360800&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-29835-y

DO - 10.1038/s41467-022-29835-y

M3 - Article

C2 - 35440579

VL - 13

JO - Nature communications

JF - Nature communications

SN - 2041-1723

IS - 1

M1 - 2136

ER -

ID: 24140918