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

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. The molecular mechanisms underlying thrombosis in acute myeloid leukemia (AML), which contribute to poor clinical outcomes, remain to be explored. Here, the authors show that hexokinase 2 (HK2)-mediated glycolysis leads to lactate-driven histone lactylation, inducing thrombosis in AML.