2. Academic Validation
  3. Graphdiyne oxide nanosheets display selective anti-leukemia efficacy against DNMT3A-mutant AML cells

Graphdiyne oxide nanosheets display selective anti-leukemia efficacy against DNMT3A-mutant AML cells

  • Nat Commun. 2022 Sep 26;13(1):5657. doi: 10.1038/s41467-022-33410-w.
Qiwei Wang # 1 2 3,  Ying Liu # 4 5 6,  Hui Wang # 5 7,  Penglei Jiang # 1 2 3,  Wenchang Qian # 1 2 3,  Min You 4 5 6,  Yingli Han 1 2 3,  Xin Zeng 1 2 3,  Jinxin Li 1 2 3,  Huan Lu 1 2 3,  Lingli Jiang 1 2 3,  Meng Zhu 1 2 3,  Shilin Li 4 5 6,  Kang Huang 5 7,  Mingmin Tang 8 9,  Xinlian Wang 4 5 6,  Liang Yan 5 10,  Zecheng Xiong 5 11,  Xinghua Shi 5 7,  Ge Bai 9,  Huibiao Liu 11,  Yuliang Li 11,  Yuliang Zhao 4 5,  Chunying Chen 12 13,  Pengxu Qian 14 15 16
Affiliations

Affiliations

  • 1 Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 2 Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.
  • 3 Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China.
  • 4 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China.
  • 5 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 6 The GBA National Institute for Nanotechnology Innovation, Guangzhou, 510700, China.
  • 7 Laboratory of Theoretical and Computational Nanoscience, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China.
  • 8 Institute of Brain and Cognition, Zhejiang University City College School of Medicine, Hangzhou, 310015, China.
  • 9 The MOE Frontier Research Center of Brain & Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou, 310058, China.
  • 10 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics and National Center for Nanoscience and Technology of China, Chinese Academy of Sciences, Beijing, 100049, China.
  • 11 Beijing National Laboratory for Molecular Sciences, Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
  • 12 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China. chenchy@nanoctr.cn.
  • 13 University of Chinese Academy of Sciences, Beijing, 100049, China. chenchy@nanoctr.cn.
  • 14 Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. axu@zju.edu.cn.
  • 15 Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China. axu@zju.edu.cn.
  • 16 Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China. axu@zju.edu.cn.
  • # Contributed equally.
PMID: 36163326 DOI: 10.1038/s41467-022-33410-w
Abstract

DNA Methyltransferase 3 A (DNMT3A) is the most frequently mutated gene in acute myeloid leukemia (AML). Although chemotherapy agents have improved outcomes for DNMT3A-mutant AML patients, there is still no targeted therapy highlighting the need for further study of how DNMT3A mutations affect AML phenotype. Here, we demonstrate that cell adhesion-related genes are predominantly enriched in DNMT3A-mutant AML cells and identify that graphdiyne oxide (GDYO) display an anti-leukemia effect specifically against these mutated cells. Mechanistically, GDYO directly interacts with Integrin β2 (ITGB2) and c-type Mannose Receptor (MRC2), which facilitate the attachment and cellular uptake of GDYO. Furthermore, GDYO binds to actin and prevents actin polymerization, thus disrupting the actin Cytoskeleton and eventually leading to cell Apoptosis. Finally, we validate the in vivo safety and therapeutic potential of GDYO against DNMT3A-mutant AML cells. Collectively, these findings demonstrate that GDYO is an efficient and specific drug candidate against DNMT3A-mutant AML.

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