Brg1 and npm-alk are co-regulated in anaplastic large-cell lymphoma; brg1 is a potential therapeutic target in alcl

Gavin D. Garland; Stephen P. Ducray; Leila Jahangiri; Perla Pucci; G. A.Amos Burke; Jack Monahan; Raymond Lai; Olaf Merkel; Ana Iris Schiefer; Lukas Kenner; Andrew J. Bannister; Suzanne D. Turner

doi:10.3390/cancers14010151

Brg1 and npm-alk are co-regulated in anaplastic large-cell lymphoma; brg1 is a potential therapeutic target in alcl

Gavin D. Garland, Stephen P. Ducray, Leila Jahangiri, Perla Pucci, G. A.Amos Burke, Jack Monahan, Raymond Lai, Olaf Merkel, Ana Iris Schiefer, Lukas Kenner, Andrew J. Bannister, Suzanne D. Turner^*

^*Corresponding author for this work

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL.

Original language	English
Article number	151
Number of pages	15
Journal	Cancers
Volume	14
Issue number	1
DOIs	https://doi.org/10.3390/cancers14010151
Publication status	Published - 29 Dec 2021

Bibliographical note

Funding Information:
Funding: This research was funded by European Union Marie Sklordowski Curie Innovative Training Network ALKATRAS, grant number 675712. S.D.T. receives funding from the CRUK Cambridge Centre Major Centre Award, grant number C9685/A25117. A.J.B. is supported by grants from Cancer Research UK (RG96894 and C6946/A24843) and the Wellcome Trust (WT203144).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

ALCL
Brg1
NPM-ALK

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

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title = "Brg1 and npm-alk are co-regulated in anaplastic large-cell lymphoma; brg1 is a potential therapeutic target in alcl",

abstract = "Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL.",

keywords = "ALCL, Brg1, NPM-ALK",

author = "Garland, {Gavin D.} and Ducray, {Stephen P.} and Leila Jahangiri and Perla Pucci and Burke, {G. A.Amos} and Jack Monahan and Raymond Lai and Olaf Merkel and Schiefer, {Ana Iris} and Lukas Kenner and Bannister, {Andrew J.} and Turner, {Suzanne D.}",

note = "Funding Information: Funding: This research was funded by European Union Marie Sklordowski Curie Innovative Training Network ALKATRAS, grant number 675712. S.D.T. receives funding from the CRUK Cambridge Centre Major Centre Award, grant number C9685/A25117. A.J.B. is supported by grants from Cancer Research UK (RG96894 and C6946/A24843) and the Wellcome Trust (WT203144). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

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AU - Garland, Gavin D.

AU - Ducray, Stephen P.

AU - Jahangiri, Leila

AU - Pucci, Perla

AU - Burke, G. A.Amos

AU - Monahan, Jack

AU - Lai, Raymond

AU - Merkel, Olaf

AU - Schiefer, Ana Iris

AU - Kenner, Lukas

AU - Bannister, Andrew J.

AU - Turner, Suzanne D.

N1 - Funding Information: Funding: This research was funded by European Union Marie Sklordowski Curie Innovative Training Network ALKATRAS, grant number 675712. S.D.T. receives funding from the CRUK Cambridge Centre Major Centre Award, grant number C9685/A25117. A.J.B. is supported by grants from Cancer Research UK (RG96894 and C6946/A24843) and the Wellcome Trust (WT203144). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/12/29

Y1 - 2021/12/29

N2 - Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL.

AB - Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL.

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ER -

Brg1 and npm-alk are co-regulated in anaplastic large-cell lymphoma; brg1 is a potential therapeutic target in alcl

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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