Hexokinase 2-mediated histone H3K18la promotes PAI-1-dependent thrombosis in acute myeloid leukemia via tumor-endothelial crosstalk

Qin Bai, Yu-Xiang Qiu, Huan Zeng, Li-Hua Yao, Fang-Min Zhong, Yan-Mei Xu, Jing Zhang, Bo Huang, Jing Liu, Hang Shi, Xuan Hou, Zi-Hao Wang, Ke-Yu Deng and Xiao-Zhong Wang ()
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Qin Bai: Nanchang University, Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College
Yu-Xiang Qiu: Nanchang University, Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College
Huan Zeng: Nanchang University, Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College
Li-Hua Yao: Nanchang University, Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College
Fang-Min Zhong: Nanchang University, Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College
Yan-Mei Xu: Nanchang University, Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College
Jing Zhang: Nanchang University, Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College
Bo Huang: Nanchang University, Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College
Jing Liu: Nanchang University, Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College
Hang Shi: Nanchang University, Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College
Xuan Hou: Nanchang University, Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College
Zi-Hao Wang: Nanchang University, Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College
Ke-Yu Deng: Nanchang University, The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College
Xiao-Zhong Wang: Nanchang University, Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Acute myeloid leukemia is an aggressive hematological malignancy frequently complicated by coagulation disorders, including thrombosis and hemorrhage, which contribute to poor outcomes. Here, we identify lactate-driven histone lactylation as a mechanism promoting thrombosis in acute myeloid leukemia. We demonstrate that hexokinase 2-mediated glycolysis in leukemic cells leads to lactate accumulation, which enhances histone H3 lysine 18 lactylation and upregulates plasminogen activator inhibitor-1 expression, impairing fibrinolysis. Lactate released by acute myeloid leukemia cells is internalized by vascular endothelial cells via monocarboxylate transporter 1, amplifying plasminogen activator inhibitor-1 expression and thrombotic risk. Inhibition of hexokinase 2-mediated lactate production or monocarboxylate transporter 1-mediated lactate uptake attenuates thrombosis. Our findings reveal a critical link between tumor metabolism, epigenetic modifications, and coagulation dysfunction in acute myeloid leukemia.

Date: 2025
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DOI: 10.1038/s41467-025-65259-0

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