Utilizing the FMS-like tyrosine kinase 3 (FLT3) gene internal tandem duplication (ITD) (FLT3-ITD) knock-in mouse and FLT3-ITD+ AML patient-derived xenograft (PDX) models that recapitulate features of human FLT3-ITD+ AML, we report here on previously unrecognized non-genetic, extrinsic mechanisms of treatment resistance in LSCs that involve the vascular compartment of the leukemic BM niche and that are mediated by a TNFα-miR-126 axis in the BM endothelial cells (ECs). This evidence concerns the gene FLT3 and acute myeloid leukemia.