It was demonstrated that Hif-1α and Hif-2α through their interaction with the “hypoxia responsive elements” (HREs) of various genes (e.g., TGFβ, c-Kit, FGF-2, VEGF, and Notch-1) may upregulate the expression of CXCR4 and CXCL12 on AML cells and endothelial cells, thereby promoting LSC maintenance and disease aggressiveness [46–48] (Figure 2). This evidence concerns the gene CXCR4 and acute myeloid leukemia.