Fig. 2 |. The leukaemia bone marrow microenvironment.

Leukaemia cell homing is mediated by the chemokine stromal cell-derived factor 1 (SDF1)^9,99–101 and adhesion molecules such as the integrin VLA-4^8,53–55 and E-selectin⁹ expressed by the vascular endothelium of fenestrated, sinusoidal bone marrow¹⁵³ vessels. In this niche, growth factors, cytokines, extracellular matrix (ECM) components as well as stromal cells such as NG2⁺ cells, pericytes and colony stimulating factor 1 receptor-positive (CSF1R⁺) monocytes¹¹⁷ all serve to promote leukaemia cell growth and survival. As leukaemia cells colonize the bone marrow (BM), they deplete resident haematopoietic stem and progenitor cells (HSPCs) through the secretion of stem cell factor (SCF), creating a malignant niche that disrupts normal haematopoiesis¹²³. Leukaemia cells may also migrate to pro-dormancy endosteal niches where osteopontin (OPN)³⁵, transforming growth factor-β (TGFβ)²³⁸ and hypoxic conditions support a quiescent state, thus protecting them from chemotherapy. Niche factors such as granulocyte colony-stimulating factor (G-CSF) can mobilize leukaemia cells from the metastatic niche into circulation where they can seed distant sites^201–203. Matrix-degrading enzymes such as elastase¹⁴³, matrix metalloproteinase 2 (MMP2)⁹² and MMP9 (REFS^90,239) can facilitate the extravasation process. Finally, immune cells such as natural killer (NK) cells may limit the survival of leukaemia cells in the BM^240,241. PSGL1, P-selectin glycoprotein ligand 1; VCAM1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor.