Abstract
Simple SummaryT-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.
Highlights
Anaplastic large-cell lymphoma (ALCL) is a T cell Non-Hodgkin Lymphoma (NHL) which accounts for 10–15% of paediatric/adolescent cases [1], and which can be separated into two distinct subclasses based on differential expression of anaplastic lymphoma kinase (ALK)
For the majority of ALK+ ALCL cases, expression of ALK is the consequence of the t(2;5)(p23;q35) chromosomal translocation that results in the fusion of ALK with nucleophosmin 1 (NPM), thereby generating the nucleophosmin–anaplastic lymphoma kinase (NPM-ALK) protein chimaera with strong expression driven by the NPM promoter, and oligomerisation potential that permits constitutive activation of NPM-ALK tyrosine kinase activity [5,6]
It has already been reported that Brg1 forms a complex with NPM-ALK as it has been detected by mass spectrometry of NPM1 immunoprecipitates in an ALCL cell line [14] and NPM1 has been identified by mass spectrometry in anti-FLAG immunoprecipitates prepared from nuclear extracts of 293T cells that ectopically express FLAG-Brg1 [33]
Summary
Anaplastic large-cell lymphoma (ALCL) is a T cell Non-Hodgkin Lymphoma (NHL) which accounts for 10–15% of paediatric/adolescent cases [1], and which can be separated into two distinct subclasses based on differential expression of anaplastic lymphoma kinase (ALK). Both subclasses share similar histological features, ALK+ ALCL patients are typically children or young adults and have a relatively good prognosis, with 88–95% of patients achieving complete remission [2,3], whereas ALK- ALCL patients are usually 40–65 years of age at diagnosis and have a less favourable prognosis, with a 5 year overall survival of 49% [4]. The molecular mechanisms accounting for transcriptional regulation in ALCL, and the role played by NPM-ALK in mediating these, largely remain to be determined, STAT3 has been shown to play a key role in ALCL [15,16]
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