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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月19日

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  • 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,
  • Xiao-Zhong Wang

摘要

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.