Shuanghong Zhu, Yingwan Luo, Kongfei Li, Chen Mei, Yuxia Wang, Lingxu Jiang, Wei Wang, Qi Zhang, Wenli Yang, Wei Lang, Xinping Zhou, Lu Wang, Yanling Ren, Liya Ma, Li Ye, Xin Huang, Jianjun Chen, Jie Sun, Hongyan Tong
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...
April 19, 2024: Science Advances