The crosstalk between leukemic cells and the microenvironment. Several studies suggest a causative role of the BM microenvironment in leukemogenesis (Initiation), mediated by alterations of signaling pathways in specific cell types, involving, for example, β-catenin, Jagged1, Ptpn11, Dicer1 in osteoblastic cells, RBPJ in endothelial cells, retinoic acid receptor-γ (RARγ) and Notch in stroma. In addition, LSC coopt existing strategies normally used by HSCs to interact with the microenvironment to proliferate and survive (Expansion and Chemoresistance). For example, LSC use adhesion molecules (CD44 and VLA-4) to bind the extracellular matrix and stroma cells, and CXCR4 to bind the abundantly secreted CXCL12. Both mechanisms enable leukemia cell migration. Leukemia also shapes the microenvironment (Remodeling) by creating a proinflammatory milieu, impairing MSC differentiation and destroying key HSC-supportive niches. As a result, HSCs intravasate, whereas leukemia cells remain within the parenchyma. LC, leukemic cell; MDS, myelodysplastic syndrome; SNS, sympathetic nervous system; TNF, tumor necrosis factor.