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.

CBMed 8010 Graz Austria

Central European Institute of Technology Masaryk University 601 77 Brno Czech Republic

Christian Doppler Laboratory of Applied Metabolomics Medical University Vienna 1090 Vienna Austria

Department of Laboratory Medicine and Pathology University of Alberta Edmonton AB T6G 2R3 Canada

Department of Life Sciences Birmingham City University Birmingham B15 3TN UK

Department of Paediatric Oncology Cambridge University Hospital NHS Trust Cambridge CB5 8PD UK

Department of Pathology Medical University Vienna 1090 Vienna Austria

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Cambridge CB2 0QQ UK

The European Bioinformatics Institute Wellcome Genome Campus Cambridge CB10 1SA UK

The Gurdon Institute Cambridge CB2 1QN UK

Unit of Pathology of Laboratory Animals University of Veterinary Medicine Vienna 1210 Vienna Austria

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