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; Pengxu Qian

doi:10.1038/s41467-022-33410-w

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 BaiHuibiao Liu, Yuliang Li, Yuliang Zhao, Chunying Chen, Pengxu Qian

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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.

Original language	English (US)
Article number	5657
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33410-w
State	Published - Dec 2022

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-022-33410-w

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Wang, Q., Liu, Y., Wang, H., Jiang, P., Qian, W., You, M., Han, Y., Zeng, X., Li, J., Lu, H., Jiang, L., Zhu, M., Li, S., Huang, K., Tang, M., Wang, X., Yan, L., Xiong, Z., Shi, X., ... Qian, P. (2022). Graphdiyne oxide nanosheets display selective anti-leukemia efficacy against DNMT3A-mutant AML cells. Nature Communications, 13(1), Article 5657. https://doi.org/10.1038/s41467-022-33410-w

Wang, Q, Liu, Y, Wang, H, Jiang, P, Qian, W, You, M, Han, Y, Zeng, X, Li, J, Lu, H, Jiang, L, Zhu, M, Li, S, Huang, K, Tang, M, Wang, X, Yan, L, Xiong, Z, Shi, X, Bai, G, Liu, H, Li, Y, Zhao, Y, Chen, C & Qian, P 2022, 'Graphdiyne oxide nanosheets display selective anti-leukemia efficacy against DNMT3A-mutant AML cells', Nature Communications, vol. 13, no. 1, 5657. https://doi.org/10.1038/s41467-022-33410-w

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title = "Graphdiyne oxide nanosheets display selective anti-leukemia efficacy against DNMT3A-mutant AML cells",

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.",

author = "Qiwei Wang and Ying Liu and Hui Wang and Penglei Jiang and Wenchang Qian and Min You and Yingli Han and Xin Zeng and Jinxin Li and Huan Lu and Lingli Jiang and Meng Zhu and Shilin Li and Kang Huang and Mingmin Tang and Xinlian Wang and Liang Yan and Zecheng Xiong and Xinghua Shi and Ge Bai and Huibiao Liu and Yuliang Li and Yuliang Zhao and Chunying Chen and Pengxu Qian",

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T1 - Graphdiyne oxide nanosheets display selective anti-leukemia efficacy against DNMT3A-mutant AML cells

AU - Wang, Qiwei

AU - Liu, Ying

AU - Wang, Hui

AU - Jiang, Penglei

AU - Qian, Wenchang

AU - You, Min

AU - Han, Yingli

AU - Zeng, Xin

AU - Li, Jinxin

AU - Lu, Huan

AU - Jiang, Lingli

AU - Zhu, Meng

AU - Li, Shilin

AU - Huang, Kang

AU - Tang, Mingmin

AU - Wang, Xinlian

AU - Yan, Liang

AU - Xiong, Zecheng

AU - Shi, Xinghua

AU - Bai, Ge

AU - Liu, Huibiao

AU - Li, Yuliang

AU - Zhao, Yuliang

AU - Chen, Chunying

AU - Qian, Pengxu

PY - 2022/12

Y1 - 2022/12

N2 - 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.

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

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