2. Academic Validation
  3. Oridonin inhibits DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia by inducing apoptosis and necroptosis

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

  • Cell Death Discov. 2021 Oct 18;7(1):297. doi: 10.1038/s41420-021-00697-5.
Min Liao 1,  Qiongye Dong 2,  Ruiqing Chen 1,  Liqian Xu 1,  Yuxuan Jiang 1,  Zhenxing Guo 3,  Min Xiao 4,  Wei He 1,  Changcai Cao 5,  Ronghua Hu 6,  Wanling Sun 7,  Hong Jiang 8,  Jianwei Wang 9
Affiliations

Affiliations

  • 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.
  • 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.
  • 7 Department of Hematology, Xuanwu Hospital, Capital Medical University, 100053, Beijing, China. wanlingsun@xwhosp.org.
  • 8 Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, 310003, Hangzhou, China. jianghong961106@zju.edu.cn.
  • 9 School of Pharmaceutical Sciences, Tsinghua University, 100084, Beijing, China. jianweiwang@tsinghua.edu.cn.
PMID: 34663800 DOI: 10.1038/s41420-021-00697-5
Abstract

DNA (cytosine-5)-methyltransferase 3A (DNMT3A) mutations occur in ~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 µM) 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.

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