The Biology Of Multiple Myeloma

The bone marrow microenvironment consists of extracellular matrix proteins, stromal cells, monoclonal myeloma cells, vascular endothelial cells, osteoblasts, osteoclasts, and lymphocytes. The interactions among the myeloma cells, stromal cells, adhesion molecules, cytokines, and the factors involved in angiogenesis play a key role in the pathogenesis of MM and in the refractoriness of the disease.

Multiple regulatory pathways are involved in the development and progression of MM. Interleukin 6 (IL-6) is an important cytokine in myeloma cell growth and proliferation.2 Close cell-to-cell contact between myeloma cells and the bone marrow stromal cells triggers a large amount of IL-6 production that supports the growth of these cells and protects them from apop-tosis induced by dexamethasone or other chemothera-peutic agents.3 In addition, IL-6 can enhance the effect of other osteoclastogenic factors, such as receptor activator of nuclear factor (RANK) ligand (RANKL), parathyroid-hormone-related peptide (PTHrP), macrophage inflammatory protein 1a (MIP-1a), IL-1, and tumor necrosis factor a (TNFa).

Nuclear factor kappa B (NF-kB) is a protein that is believed to be central to the pathophysiology of MM. The Rel/NF-KB family of proteins includes inducible dimeric transcription factors that recognize and bind a common sequence motif in nuclear DNA.4-7 NF-kB, the major transcription factor in this family, is a p50/RelA heterodimer (p50/p65) present in the cytoplasm of almost all cells.78 NF-kB regulates cell growth and apop-tosis, as well as the expression of various cytokines, adhesion molecules, and their receptors.9 NF-kB is normally bound in the cytoplasm to its inhibitor I-kB.7 Stimulation of cells by cytokines, stress, or chemotherapy can trigger signaling cascades that lead to activation of I-kB kinase (a heterodimeric protein kinase that catalyzes I-kB phosphorylation). I-kB is then degraded by the proteasome pathway, releasing free active NF-kB. After release from I-kB, activated NF-kB translocates to the nucleus and binds to the promoter regions of several target genes, thereby triggering their transcription. This in turn leads to increased expression of various cytokines and chemokines, adhesion molecules, and cyclin D, which promote cell growth and survival.6 NF-kB activation also leads to increased expression of adhesion molecules, such as ICAM-1 and VCAM-1 by MM cells, thus facilitating the binding of the myeloma cells to stroma, in turn causing NF-KB-mediated upregu-lation of IL-6 secretion by the stromal cells and contributing to drug resistance.1011 Therefore, treatment strategies targeting NF-kB, the malignant cell-stroma interaction, and the complex cytokine network could result in regulation of the growth and development of the MM cells.

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