Aberrant fucosylation of extracellular vesicles remodels the vascular microenvironment and promotes chemoresistance in myelodysplastic syndromes and acute myeloid leukemia

Primary resistance to hypomethylating agents (HMAs) remains a major obstacle in the treatment of elderly patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). An altered integrity of the vascular wall is suspected to contribute to this resistance, yet the underlying molecular mechanisms remain unclear. Here, we show that small extracellular vesicles (sEVs) derived from leukemic cells resistant to decitabine (DAC-R), a commonly used HMA, promote vascular permeability by downregulating tight junction proteins, including ZO-1, occludin, and claudin5, in endothelial cell monolayers. This disruption of vascular integrity may facilitate vascular leakage and leukemic cell dissemination. Mechanistically, DAC-R cells exhibit increased expression of the fucosyltransferase FUT4, driven by the transcription factor TWIST1, leading to enhanced biosynthesis of non-sialylated Lewis X (LeX) structures. FUT4-mediated LeX modification stabilizes intercellular adhesion molecule 3 (ICAM3) on sEVs, and the delivery of LeX-modified ICAM3 to endothelial cells suppresses NF-κB signaling, impairing endothelial barrier function. Functionally, vascular remodeling driven by fucosylated sEVs promotes leukemic dissemination, suggesting that disruption of vascular homeostasis represents an additional layer of therapeutic resistance. These findings define a TWIST1-FUT4-LeX-ICAM3 axis and highlight glycosylation as a critical mediator of vascular microenvironment remodeling in MDS/AML.