1. Myeloma cell interaction with extracellular matrix (ECM) and accessory cells in the marrow. Myeloma cells require support from bone marrow stromal cells (BMSCs) during early stage disease. Adhesion between myeloma cells and BMSCs favors myeloma cell survival, growth, and migration via release of cytokines (IL-6, VEGF, IGF-1, SDF1α, BAFF, APRIL, HGF, TNF-α) from both myeloma cells and BMSCs. Among others, extracellular signal-regulated kinase (ERK); Janus kinase 2 (JAK2)–signal transducer and activator of transcription 3 (STAT3); phosphatidylinositol 3′-kinase (PI3K)–Akt; nuclear factor-κB (NF-κB) and MYC are constitutively active in myeloma, promoting transcription or activation of important targets, including cytokines (IL-6, IGF-1, VEGF); antiapoptotic proteins (BCL-XL, IAP, MCL1); cell-cycle modulators (cyclin D1); and proteins involved in migration, invasion, and autophagy. NF-κB activation in both myeloma and BMSCs upregulates adhesion molecules (VCAM1, VLA4) to promote reciprocal binding. Proangiogenic factors, including VEGF and HGF, are released from myeloma cells, BMSCs, and marrow endothelial cells to promote neoangiogenesis and increase delivery of oxygen and nutrients to tumor cells. Cells from the innate and adaptive immune response, including B lymphocytes, T lymphocytes, dendritic cells, and myeloid-derived suppressor cells, are also modulated by myeloma cells, creating an immunosuppressive microenvironment that promotes tumor survival and reduces antigen-presenting capabilities. Receptor activator of NF-κB ligand (RANKL) and MIP-1α are produced by BMSCs and myeloma cells and trigger osteoclast activation via RANK receptor. Osteoprotegerin (OPG), a decoy receptor for RANKL secreted by osteoblasts and BMSCs to block RANKL–RANK ligand interaction and inhibit osteoclastogenesis, is reduced in myeloma patients. APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; BCL-XL, B-cell lymphoma-extra large; FKHR, forkhead in rhabdomyosarcoma; GSK3B, glycogen synthase kinase 3 beta; HGF, human growth factor; IAP, inhibitors of apoptosis proteins; IGF-1, insulin-like growth factor; IL, interleukin; MCL1, myeloid leukemia cell differentiation protein 1; MIP, macrophage inflammatory protein; mTOR, mammalian target of rapamycin; PKC, protein kinase C; SDF1α, stromal cell–derived factor 1α; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor; VLA, very-late antigen.
Source: Myeloma, Williams Hematology Malignant Lymphoid Diseases
Citation: Press OW, Lichtman MA, Leonard JP. Williams Hematology Malignant Lymphoid Diseases; 2017 Available at: Accessed: January 05, 2018
Copyright © 2018 McGraw-Hill Education. All rights reserved