坏死性下垂
脱甲基酶
裂谷1
程序性细胞死亡
髓系白血病
癌症研究
组蛋白H3
IDH1
癸他滨
化学
组蛋白
细胞凋亡
生物
细胞生物学
突变体
生物化学
DNA甲基化
基因表达
基因
作者
Hongyan Tong,Yingwan Luo,Kongfei Li,Mei Chen,Yuxia Wang,Liyan Jiang,Wei Wang,Q.H. Zhang,Wen Qing Yang,Wei Lang,Xinping Zhou,Lu Hua Wang,Yanling Ren,Liya Ma,Lijiao Ye,Xin Huang,Jianjun Chen,Jie Sun,Hongyan Tong
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2024-04-19
卷期号:10 (16)
标识
DOI:10.1126/sciadv.adi1782
摘要
Mutant isocitrate dehydrogenases (IDHs) produce R-2-hydroxyglutarate (R-2HG), which inhibits the growth of most acute myeloid leukemia (AML) cells. Here, we showed that necroptosis, a form of programmed cell death, contributed to the antileukemia activity of R-2HG. Mechanistically, R-2HG competitively inhibited the activity of lysine demethylase 2B (KDM2B), an α-ketoglutarate–dependent dioxygenase. KDM2B inhibition increased histone 3 lysine 4 trimethylation levels and promoted the expression of receptor-interacting protein kinase 1 (RIPK1), which consequently caused necroptosis in AML cells. The expression of RIPK3 was silenced because of DNA methylation in IDH-mutant (mIDH) AML cells, resulting in R-2HG resistance. Decitabine up-regulated RIPK3 expression and repaired endogenous R-2HG–induced necroptosis pathway in mIDH AML cells. Together, R-2HG induced RIPK1-dependent necroptosis via KDM2B inhibition in AML cells. The loss of RIPK3 protected mIDH AML cells from necroptosis. Restoring RIPK3 expression to exert R-2HG’s intrinsic antileukemia effect will be a potential therapeutic strategy in patients with AML.
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