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

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.