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

Qiwei Wang, Ying Liu, Hui Wang, Penglei Jiang, Wenchang Qian, Min You, Yingli Han, Xin Zeng, Jinxin Li, Huan Lu, Lingli Jiang, Meng Zhu, Shilin Li, Kang Huang, Mingmin Tang, Xinlian Wang, Liang Yan, Zecheng Xiong, Xinghua Shi, Ge Bai, Huibiao Liu, Yuliang Li, Yuliang Zhao, Chunying Chen () and Pengxu Qian ()
Additional contact information
Qiwei Wang: Zhejiang University School of Medicine
Ying Liu: National Center for Nanoscience and Technology of China
Hui Wang: University of Chinese Academy of Sciences
Penglei Jiang: Zhejiang University School of Medicine
Wenchang Qian: Zhejiang University School of Medicine
Min You: National Center for Nanoscience and Technology of China
Yingli Han: Zhejiang University School of Medicine
Xin Zeng: Zhejiang University School of Medicine
Jinxin Li: Zhejiang University School of Medicine
Huan Lu: Zhejiang University School of Medicine
Lingli Jiang: Zhejiang University School of Medicine
Meng Zhu: Zhejiang University School of Medicine
Shilin Li: National Center for Nanoscience and Technology of China
Kang Huang: University of Chinese Academy of Sciences
Mingmin Tang: Zhejiang University City College School of Medicine
Xinlian Wang: National Center for Nanoscience and Technology of China
Liang Yan: University of Chinese Academy of Sciences
Zecheng Xiong: University of Chinese Academy of Sciences
Xinghua Shi: University of Chinese Academy of Sciences
Ge Bai: Zhejiang University School of Brain Science and Brain Medicine
Huibiao Liu: Chinese Academy of Sciences
Yuliang Li: Chinese Academy of Sciences
Yuliang Zhao: National Center for Nanoscience and Technology of China
Chunying Chen: National Center for Nanoscience and Technology of China
Pengxu Qian: Zhejiang University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33410-w

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