机构：[1]School of Pharmaceutical Sciences, Tsinghua University, 100084 Beijing, China.[2]Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, 100190 Beijing, China.[3]Department of Hematology/Oncology, First Hospital of Tsinghua University, 100016 Beijing, China.[4]Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China.华中科技大学同济医学院附属同济医院[5]Shandong Hongmai Biotechnology Co., Ltd. Room 1201, building B, Research Institute of Tianjin University, No. 51, Lutai Avenue, Zibo High tech Zone, 255000 Tianjin, China.[6]Department of Hematology, Xuanwu Hospital, Capital Medical University, 100053 Beijing, China.内科系统血液科首都医科大学宣武医院[7]Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, 310003 Hangzhou, China.浙江大学医学院附属第一医院
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.
基金：
National Institute of Biological Sciences) for providing
RIPA56. We thank the Beijing Advanced Innovation Center for Structural Biology and
the Tsinghua-Peking Center for Life Sciences for facility and financial support. This
work was supported by grant numbers 81870118, 2018YFA0800200, 91849106,
Z200022, Z181100001818005, and 2017YFA0104000 to J.W. from the National Natural
Science Foundation of China, the National Key R&D Program of China, and the Beijing
Municipal Science & Technology Commission.
第一作者机构：[1]School of Pharmaceutical Sciences, Tsinghua University, 100084 Beijing, China.
通讯作者：
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):doi:10.1038/s41420-021-00697-5.
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)
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)
