Oridonin inhibits DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia by inducing apoptosis and necroptosis

doi:10.1038/s41420-021-00697-5

	Oridonin inhibits DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia by inducing apoptosis and necroptosis
	Liao, Min 1; Dong, Qiongye 2; Chen, Ruiqing 1; Xu, Liqian 1; Jiang, Yuxuan 1; Guo, Zhenxing 3; Xiao, Min 4; He, Wei 1; Cao, Changcai 5; Hu, Ronghua 6
刊名	CELL DEATH DISCOVERY
	2021-10-18
卷号	7 期号:1 页码:12
DOI	10.1038/s41420-021-00697-5
英文摘要	DNA (cytosine-5)-methyltransferase 3A (DNMT3A) mutations occur in similar to 20% of de novo acute myeloid leukemia (AML) patients, and >50% of these mutations in AML samples are heterozygous missense alterations within the methyltransferase domain at residue R882. DNMT3A R882 mutations in AML patients promote resistance to anthracycline chemotherapy and drive relapse. In this study, we performed high-throughput screening and identified that oridonin, an ent-kaurene diterpenoid extracted from the Chinese herb Rabdosia rubescens, inhibits DNMT3A R882 mutant leukemic cells at a low-micromolar concentration (IC50 = 2.1 mu M) by activating both RIPK1-Caspase-8-Caspase-3-mediated apoptosis and RIPK1-RIPK3-MLKL-mediated necroptosis. The inhibitory effect of oridonin against DNMT3A R882 mutant leukemia cells can also be observed in vivo. Furthermore, oridonin inhibits clonal hematopoiesis of hematopoietic stem cells (HSCs) with Dnmt3a R878H mutation comparing to normal HSCs by inducing apoptosis and necroptosis. Overall, oridonin is a potential and promising drug candidate or lead compound targeting DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia.
资助项目	Beijing Advanced Innovation Center for Structural Biology ; Tsinghua-Peking Center for Life Sciences ; National Natural Science Foundation of China[81870118] ; National Natural Science Foundation of China[2018YFA0800200] ; National Natural Science Foundation of China[91849106] ; National Natural Science Foundation of China[Z200022] ; National Natural Science Foundation of China[Z181100001818005] ; National Natural Science Foundation of China[2017YFA0104000] ; National Key R&D Program of China ; Beijing Municipal Science & Technology Commission
WOS研究方向	Cell Biology
语种	英语
出版者	SPRINGERNATURE
WOS记录号	WOS:000708486600001
内容类型	期刊论文
源URL	[http://119.78.100.204/handle/2XEOYT63/16992]
专题	中国科学院计算技术研究所
通讯作者	Sun, Wanling; Jiang, Hong; Wang, Jianwei
作者单位	1.Tsinghua Univ, Sch Pharmaceut Sci, Beijing 100084, Peoples R China 2.Chinese Acad Sci, Adv Comp Res Ctr, Inst Comp Technol, Key Lab Intelligent Informat Proc, Beijing 100190, Peoples R China 3.Tsinghua Univ, Dept Hematol Oncol, Hosp 1, Beijing 100016, Peoples R China 4.Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Hematol, Wuhan 430030, Peoples R China 5.Tianjin Univ, Res Inst, Shandong Hongmai Biotechnol Co Ltd, Room 1201,Bldg B,51 Lutai Ave, Tianjin 255000, Peoples R China 6.Capital Med Univ, Xuanwu Hosp, Dept Hematol, Beijing 100053, Peoples R China 7.Zhejiang Univ, Affiliated Hosp 1, Coll Med, Kidney Dis Ctr, Hangzhou 310003, Peoples R China
推荐引用方式 GB/T 7714	Liao, Min,Dong, Qiongye,Chen, Ruiqing,et al. Oridonin inhibits DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia by inducing apoptosis and necroptosis[J]. CELL DEATH DISCOVERY,2021,7(1):12.
APA	Liao, Min.,Dong, Qiongye.,Chen, Ruiqing.,Xu, Liqian.,Jiang, Yuxuan.,...&Wang, Jianwei.(2021).Oridonin inhibits DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia by inducing apoptosis and necroptosis.CELL DEATH DISCOVERY,7(1),12.
MLA	Liao, Min,et al."Oridonin inhibits DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia by inducing apoptosis and necroptosis".CELL DEATH DISCOVERY 7.1(2021):12.