Exosomal PKM2 from AML cells reprograms endothelial metabolism to promote angiogenesis and chemoresistance.

In acute myeloid leukemia (AML), therapeutic resistance is intimately linked to vascular microenvironment remodeling; however, the initiating molecular determinants remain elusive. Here, we identified exosomal pyruvate kinase M2 (PKM2) as a pivotal mediator of this pathogenic process. PKM2 was abundantly present in AML-derived exosomes and transferred to human umbilical vein endothelial cells (HUVECs), eliciting metabolic reprogramming characterized by enhanced glycolysis and angiogenic activation. Mechanistically, PKM2 knockdown in AML cells substantially attenuated exosome-induced endothelial migration and tube formation, whereas ectopic PKM2 overexpression in endothelial cells potentiated pro-angiogenic phenotypes. In NOD/SCID mouse xenograft, AML-derived exosomes promoted microvascular remodeling and accelerated disease progression, effects that were abrogated by the angiogenesis inhibitor endostatin. This vascular remodeling coincided with diminished cytarabine (Ara-C) sensitivity, indicative of a chemoprotective microenvironment. Consistently, in a systemic AML model, pharmacological PKM2 inhibition disrupted the vascular niche, suppressed angiogenesis, and restored Ara-C chemosensitivity. Clinically, PKM2 expression correlated positively with VEGFA and HIF-1α levels, and exosomes derived from AML patients with elevated PKM2 conferred enhanced tube-forming capacity upon endothelial cells. Collectively, these findings establish exosomal PKM2 as a critical regulator of the chemoprotective vascular niche in AML and underscore its translational potential as a therapeutic target.