LDLRAD2 drives glycolysis and angiogenesis to promote extramedullary infiltration in acute myeloid leukemia.

Acute myeloid leukemia (AML) remodels the bone marrow microenvironment and can spread to extramedullary sites, a feature associated with adverse clinical outcomes. Here, we identify low-density lipoprotein receptor class A domain-containing 2 (LDLRAD2) as a driver of extramedullary infiltration (EMI) through analyses of patient samples, public datasets, AML cell models, and xenografts. LDLRAD2 increased glucose consumption, lactate production, endothelial tube formation, spleen infiltration, and microvascular density, whereas its knockdown reduced these phenotypes. Mechanistically, LDLRAD2 interacted with metadherin (MTDH) and activated PI3K/AKT/mTOR signaling, thereby promoting glycolysis, angiogenesis, and EMI. Inhibition of LDLRAD2 or treatment with 2-deoxyglucose suppressed glycolysis-associated angiogenic effects. These findings support LDLRAD2-associated metabolic and angiogenic remodeling as a mechanism underlying EMI in AML and highlight a potential therapeutic vulnerability.