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EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) causes HTLV-1-associated myelopathy (HAM), adult T-cell leukemia/lymphoma (ATL), HTLV-1-associated uveitis, and pulmonary diseases. Although both HAM and ATL show proliferation of infected cells, their pathogeneses are quite different. In parti...

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Autores principales: Koseki, Akihito, Araya, Natsumi, Yamagishi, Makoto, Yamauchi, Junji, Yagishita, Naoko, Takao, Naoki, Takahashi, Katsunori, Kunitomo, Yasuo, Honma, Daisuke, Araki, Kazushi, Uchimaru, Kaoru, Sato, Tomoo, Yamano, Yoshihisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10291084/
https://www.ncbi.nlm.nih.gov/pubmed/37378292
http://dx.doi.org/10.3389/fmicb.2023.1175762
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author Koseki, Akihito
Araya, Natsumi
Yamagishi, Makoto
Yamauchi, Junji
Yagishita, Naoko
Takao, Naoki
Takahashi, Katsunori
Kunitomo, Yasuo
Honma, Daisuke
Araki, Kazushi
Uchimaru, Kaoru
Sato, Tomoo
Yamano, Yoshihisa
author_facet Koseki, Akihito
Araya, Natsumi
Yamagishi, Makoto
Yamauchi, Junji
Yagishita, Naoko
Takao, Naoki
Takahashi, Katsunori
Kunitomo, Yasuo
Honma, Daisuke
Araki, Kazushi
Uchimaru, Kaoru
Sato, Tomoo
Yamano, Yoshihisa
author_sort Koseki, Akihito
collection PubMed
description BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) causes HTLV-1-associated myelopathy (HAM), adult T-cell leukemia/lymphoma (ATL), HTLV-1-associated uveitis, and pulmonary diseases. Although both HAM and ATL show proliferation of infected cells, their pathogeneses are quite different. In particular, the pathogenesis of HAM is characterized by hyperimmune responses to HTLV-1-infected cells. Recently, we demonstrated the overexpression of histone methyltransferase EZH2 in ATL cells and the cytotoxic effects of EZH2 inhibitors and EZH1/2 dual inhibitors on these cells. However, these phenomena have never been studied in HAM. Furthermore, what effect these agents have on the hyperimmune response seen in HAM is completely unknown. METHODS: In this study, we investigated histone methyltransferase expression levels in infected cell populations (CD4(+) and CD4(+)CCR4(+) cells) from patients with HAM using microarray and RT-qPCR analyses. Next, using an assay system that utilizes the spontaneous proliferation characteristic of peripheral blood mononuclear cells derived from patients with HAM (HAM-PBMCs), we investigated the effects of EZH2 selective inhibitors (GSK126 and tazemetostat) and EZH1/2 dual inhibitors (OR-S1 and valemetostat, also known as DS-3201), particularly on cell proliferation rate, cytokine production, and HTLV-1 proviral load. We also examined the effect of EZH1/2 inhibitors on the proliferation of HTLV-1-infected cell lines (HCT-4 and HCT-5) derived from patients with HAM. RESULTS: We found elevated expression of EZH2 in CD4(+) and CD4(+)CCR4(+) cells from patients with HAM. EZH2 selective inhibitors and EZH1/2 inhibitors significantly inhibited spontaneous proliferation of HAM-PBMC in a concentration-dependent manner. The effect was greater with EZH1/2 inhibitors. EZH1/2 inhibitors also reduced the frequencies of Ki67(+) CD4(+) T cells and Ki67(+) CD8(+) T cells. Furthermore, they reduced HTLV-1 proviral loads and increased IL-10 levels in culture supernatants but did not alter IFN-γ and TNF-α levels. These agents also caused a concentration-dependent inhibition of the proliferation of HTLV-1-infected cell lines derived from patients with HAM and increased annexin-V(+)7-aminoactinomycin D(−) early apoptotic cells. CONCLUSION: This study showed that EZH1/2 inhibitors suppress HTLV-1-infected cell proliferation through apoptosis and the hyperimmune response in HAM. This indicates that EZH1/2 inhibitors may be effective in treating HAM.
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spelling pubmed-102910842023-06-27 EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy Koseki, Akihito Araya, Natsumi Yamagishi, Makoto Yamauchi, Junji Yagishita, Naoko Takao, Naoki Takahashi, Katsunori Kunitomo, Yasuo Honma, Daisuke Araki, Kazushi Uchimaru, Kaoru Sato, Tomoo Yamano, Yoshihisa Front Microbiol Microbiology BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) causes HTLV-1-associated myelopathy (HAM), adult T-cell leukemia/lymphoma (ATL), HTLV-1-associated uveitis, and pulmonary diseases. Although both HAM and ATL show proliferation of infected cells, their pathogeneses are quite different. In particular, the pathogenesis of HAM is characterized by hyperimmune responses to HTLV-1-infected cells. Recently, we demonstrated the overexpression of histone methyltransferase EZH2 in ATL cells and the cytotoxic effects of EZH2 inhibitors and EZH1/2 dual inhibitors on these cells. However, these phenomena have never been studied in HAM. Furthermore, what effect these agents have on the hyperimmune response seen in HAM is completely unknown. METHODS: In this study, we investigated histone methyltransferase expression levels in infected cell populations (CD4(+) and CD4(+)CCR4(+) cells) from patients with HAM using microarray and RT-qPCR analyses. Next, using an assay system that utilizes the spontaneous proliferation characteristic of peripheral blood mononuclear cells derived from patients with HAM (HAM-PBMCs), we investigated the effects of EZH2 selective inhibitors (GSK126 and tazemetostat) and EZH1/2 dual inhibitors (OR-S1 and valemetostat, also known as DS-3201), particularly on cell proliferation rate, cytokine production, and HTLV-1 proviral load. We also examined the effect of EZH1/2 inhibitors on the proliferation of HTLV-1-infected cell lines (HCT-4 and HCT-5) derived from patients with HAM. RESULTS: We found elevated expression of EZH2 in CD4(+) and CD4(+)CCR4(+) cells from patients with HAM. EZH2 selective inhibitors and EZH1/2 inhibitors significantly inhibited spontaneous proliferation of HAM-PBMC in a concentration-dependent manner. The effect was greater with EZH1/2 inhibitors. EZH1/2 inhibitors also reduced the frequencies of Ki67(+) CD4(+) T cells and Ki67(+) CD8(+) T cells. Furthermore, they reduced HTLV-1 proviral loads and increased IL-10 levels in culture supernatants but did not alter IFN-γ and TNF-α levels. These agents also caused a concentration-dependent inhibition of the proliferation of HTLV-1-infected cell lines derived from patients with HAM and increased annexin-V(+)7-aminoactinomycin D(−) early apoptotic cells. CONCLUSION: This study showed that EZH1/2 inhibitors suppress HTLV-1-infected cell proliferation through apoptosis and the hyperimmune response in HAM. This indicates that EZH1/2 inhibitors may be effective in treating HAM. Frontiers Media S.A. 2023-06-12 /pmc/articles/PMC10291084/ /pubmed/37378292 http://dx.doi.org/10.3389/fmicb.2023.1175762 Text en Copyright © 2023 Koseki, Araya, Yamagishi, Yamauchi, Yagishita, Takao, Takahashi, Kunitomo, Honma, Araki, Uchimaru, Sato and Yamano. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Koseki, Akihito
Araya, Natsumi
Yamagishi, Makoto
Yamauchi, Junji
Yagishita, Naoko
Takao, Naoki
Takahashi, Katsunori
Kunitomo, Yasuo
Honma, Daisuke
Araki, Kazushi
Uchimaru, Kaoru
Sato, Tomoo
Yamano, Yoshihisa
EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy
title EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy
title_full EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy
title_fullStr EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy
title_full_unstemmed EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy
title_short EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy
title_sort ezh1/2 dual inhibitors suppress htlv-1-infected cell proliferation and hyperimmune response in htlv-1-associated myelopathy
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10291084/
https://www.ncbi.nlm.nih.gov/pubmed/37378292
http://dx.doi.org/10.3389/fmicb.2023.1175762
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