BRG1 and NPM-ALK Are Co-Regulated in Anaplastic Large-Cell Lymphoma; BRG1 Is a Potential Therapeutic Target in ALCL

Varování

Publikace nespadá pod Lékařskou fakultu, ale pod Středoevropský technologický institut. Oficiální stránka publikace je na webu muni.cz.

Autoři	GARLAND Gavin D DUCRAY Stephen P JAHANGIRI Leila PUCCI Perla AMOS BURKE G.A. MONAHAN Jack LAI Raymond MERKEL Olaf SCHIEFER Ana-Iris KENNER Lukas BANNISTER Andrew J TURNER Suzanne Dawn
Rok publikování	2022
Druh	Článek v odborném periodiku
Časopis / Zdroj	CANCERS
Fakulta / Pracoviště MU	Středoevropský technologický institut
Citace
www	https://www.mdpi.com/2072-6694/14/1/151
Doi	http://dx.doi.org/10.3390/cancers14010151
Klíčová slova	NPM-ALK; ALCL; Brg1
Popis	Simple Summary T-cell lymphoma is a cancer of the immune system. One specific sub-type of T-cell lymphoma is a malignancy called anaplastic large cell lymphoma (ALCL), which is distinct from the other forms, as in general, it has a better prognosis. Research conducted to understand why ALCL develops has shown that a specific genetic event occurs, whereby a new protein is created that drives tumour growth. This protein is called nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). Our research, described here, shows that NPM-ALK regulates another protein, called BRG1, to drive proliferation of tumour cells. In turn, when the gene that leads to expression of BRG1 is inactivated, the tumour cells die. These data suggest that therapeutic targeting of BRG1 might be a novel therapy for this form of cancer. 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.