Role of the BM niche in MM pathogenesis. The blue oval in the center is the MMC, with its close interplay with cellular and acellular components of the BM. The pale orange ovals represent relevant cytokines/chemokines in the BM milieu. Dotted arrows indicate differentiation, whereas solid arrows indicate secretion and/or effect on a target cell. Yellow squares contain a synopsis of the overall effect of cytokines and cell-to-cell contact on the target cell. Key signaling cascades, transmembrane proteins, and intracellular organelles, which are of interest for molecularly targeted therapies, are represented. BMSC, BM stromal cell; CAF, cancer-associated fibroblast; CCL2, chemokine (C-C motif) ligand 2; CTLA4, cytotoxic T-lymphocyte-associated protein 4; CXCL12, chemokine (C-X-C motif) ligand 12; CXCR4, chemokine (C-X-C motif) receptor 4; DKK-1, dickkopf WNT signaling pathway inhibitor 1; ER, endoplasmic reticulum; FN, fibronectin; HGF, hepatocyte growth factor; HIF-1α, hypoxia-inducible factor 1α; ICAM1, intercellular adhesion molecule 1; IGF-1, insulinlike growth factor 1; ITGB1, integrin β1; ITGB2, integrin β2; JNK, c-JUN N-terminal kinase; MAPK1, mitogen-activated protein kinase 1; MDSC, myeloid-derived suppressor cell; MIP-1α, macrophage inflammatory protein 1α; MUC-1, mucin 1; NK-T cells, natural killer T cells; OPG, osteoprotegerin; PD-1, programmed cell death 1; PD-L1, programmed ligand death 1; RANK, receptor activator of NF-κB; RANKL, RANK ligand; RBC, red blood cell; TGF-β, transforming growth factor β; TH17, T helper 17 cell; Treg, regulatory T cell; VCAM1, vascular cell adhesion molecule 1; VEGFA, vascular endothelial growth factor A; WNT, wingless-type. Adapted from Bianchi and Anderson⁴⁷  with permission.