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ID 118211
著者
Ohguchi, Hiroto Kumamoto University
Oda, Asuka Tokushima University
Maruhashi, Tomoko Tokushima University
Takahashi, Mamiko Tokushima University
賀川, 久美子 Tokushima Prefectural Central Hospital KAKEN研究者をさがす
尾崎, 修治 Tokushima Prefectural Central Hospital
Hideshima, Teru Harvard Medical School
資料タイプ
学術雑誌論文
抄録
Multiple myeloma (MM) preferentially expands and acquires drug resistance in the bone marrow (BM). We herein examined the role of histone deacetylase 1 (HDAC1) in the constitutive activation of the master transcription factor IRF4 and the prosurvival mediator PIM2 kinase in MM cells. The knockdown or inhibition of HDAC1 by the class I HDAC inhibitor MS-275 reduced the basal expression of IRF4 and PIM2 in MM cells. Mechanistically, the inhibition of HDAC1 decreased IRF4 transcription through histone hyperacetylation and inhibiting the recruitment of RNA polymerase II at the IRF4 locus, thereby reducing IRF4-targeting genes, including PIM2. In addition to the transcriptional regulation of PIM2 by the HDAC1-IRF4 axis, PIM2 was markedly upregulated by external stimuli from BM stromal cells and interleukin-6 (IL-6). Upregulated PIM2 contributed to the attenuation of the cytotoxic effects of MS-275. Class I HDAC and PIM kinase inhibitors cooperatively suppressed MM cell growth in the presence of IL-6 and in vivo. Therefore, the present results demonstrate the potential of the simultaneous targeting of the intrinsic HDAC1-IRF4 axis plus externally activated PIM2 as an efficient therapeutic option for MM fostered in the BM.
掲載誌名
Blood Advances
ISSN
24739529
24739537
出版者
The American Society of Hematology
7
6
開始ページ
1019
終了ページ
1032
発行日
2023-03-20
権利情報
© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) (https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
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フルテキストファイル
言語
eng
著者版フラグ
出版社版
部局
病院
薬学系
歯学系
医学系