Protective effect of marrow microenvironment. The Hematopoietic Inductive Microenvironment (HIM) niches include osteoblasts, stromal/mesenchymal cells, endothelial cells and extracellular matrix components. AML blast quiescence, proliferation and apoptosis are influenced by receptor kinases, adhesive receptors and signaling via matrix mediated/bound chemokines and cytokines. AMD3100 and AMD3465 CXCR4 antagonists +/− sorafenib or inhibitors of VLA-4/VCAM-1 interactions chemosensitize AML blasts within the HIM niches. Shh: sonic hedgehog, Notch, vascular endothelial factor and other adhesion receptors signals promote leukemic stem cell survival and expansion and can be targeted to overcome AML chemoresistance.