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The EZH2 inhibitor tazemetostat upregulates the expression of CCL17/TARC in B-cell lymphoma and enhances T-cell recruitment

Yuan, Hepei 京都大学 DOI:10.14989/doctor.k24496

2023.03.23

概要

An inhibitor of the histone methyltransferase enhancer of zeste homologue 2 (EZH2),
tazemetostat, has been developed for the treatment of B-­cell lymphoma, but its
mechanisms of action are not fully elucidated. We screened for genes targeted by
tazemetostat in eleven B-­cell lymphoma cell lines and found that tazemetostat significantly increased the expression of chemokine (C-­C motif) ligand 17 (CCL17)/thymus-­and activation-­regulated chemokine (TARC) in all, which codes for a chemokine
that is a hallmark of Hodgkin/Reed-­Sternberg (H/RS) cells in Hodgkin lymphoma.
Notably, gene set enrichment analysis demonstrated a positive correlation between
the genes upregulated by tazemetostat in five follicular lymphoma (FL) cell lines and
those reported to be overexpressed in H/RS cells. The CCL17 promoter region was
enriched in repressive histone modification H3K27me3, and tazemetostat induced
H3K27 demethylation and activated gene transcription. CCL17 protein secretion was
also induced by EZH2 inhibition, which was further enhanced by concurrent CpG
stimulation. In vitro transwell migration assay demonstrated that CCL17 produced
by tazemetostat-­treated B cells enhanced the recruitment of T cells, which had the
potential to exert antilymphoma response. Analysis of publicly available human lymphoma databases showed that CCL17 gene expression was inversely correlated with
the EZH2 activation signature and significantly paralleled the CD4+ and CD8+ T-­cell–­
rich signature in FL and germinal center B-­cell–­like diffuse large B-­cell lymphoma.
Our findings indicate that tazemetostat can potentially activate antilymphoma response by upregulating CCL17 expression in B-­cell lymphoma cells and promote T-­
cell recruitment, which provides a rationale for its combination with immunotherapy. ...

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参考文献

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S U P P O R T I N G I N FO R M AT I O N

Additional supporting information may be found online in the

Supporting Information section.

How to cite this article: Yuan H, Nishikori M, Otsuka Y, Arima

H, Kitawaki T, Takaori-­Kondo A. The EZH2 inhibitor

tazemetostat upregulates the expression of CCL17/TARC in

B-­cell lymphoma and enhances T-­cell recruitment. Cancer Sci.

2021;112:4604–­4616. https://doi.org/10.1111/cas.15122

...

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