Targeting Leukemia Stem Cell-Niche Dynamics: A New Challenge in AML Treatment

Figure 1

Bone marrow vascular niche. The vascular niche is composed of sinusoidal endothelial cells and mesenchymal stem cells (MSCs), both of which express adhesion molecules such as VCAM1, which bind to the corresponding receptor VLA4 (an α4β1 integrin) expressed on both HSCs and LSCs, and the soluble stem cell factor (SCF), which binds c-Kit to the surface of HSCs and LSCs. Natalizumab, an anti-VLA-4 monoclonal antibody, acts by preventing the VLA4-VCAM1 interaction. CXCL-12 is produced mainly by CXCL-12-abundant reticular cells (CARs). The binding of CXCL-12 to CXCR4 on HSCs and LSCs plays an important role in HSC and LSC homing and retention within the bone marrow. Plerixafor, which acts by inhibiting this link, promotes the HSC/LSC mobilization from the bone marrow vascular niche. E-selectin is expressed on endothelial cells and is involved in HSC/LSC retention within the bone marrow vascular niche through its interaction with sialylated carbohydrate expressed on both the HSC and LSC surfaces. GMI-1271, which is an E-selectin inhibitor, promotes HSC and LSC displacement by weakening this link. Finally, a close interaction between MSCs and adrenergic fibers has also been demonstrated. Release of noradrenaline by the sympathetic nervous system (SNS) induces metalloproteinase expression and activity, which then act to cleave other adhesion molecules (CXCR4, VLA4, VCAM1, and SCF), thereby promoting HSC release from the bone marrow [39, 40].