The Biological Effect Of Human Multiple Myeloma Cells Expressing CD40L/CD40 And CD40 Mutants

Multiple myeloma (MM) is a progressive and fatal neoplasm of B cell lineage, characterized by clonal expansion of malignant plasma cells in the bone marrow and their egress into peripheral blood with progression to plasma cell leukemia. It has been shown that IL-6 of autocrine or paracrine origin is a primary growth factor for MM cells in vitro and in vivo.CD40, a member of the tumor necrosis factor (TNF) receptor superfamily, is a 50kD transmembrane glycoprotein, originally identified in B lymphocytes, monocytes, macrophages and dendritic cells (DCs) as well as in some B cell malignancies. B lymphocytes normally lose CD40 expression during B cells differentiation into plasma cells. CD40 ligand (CD40L) is expressed mainly in activated CD4+T cells as well as in activated platelets. Functional studies have demonstrated that the CD40-CD40L pathway acts as an important costimulatory factor in the regulation of the immune response, such as long-term in vitro B cell proliferation, immunoglobulin class switching, antibody secretion, and rescue from apoptosis at different time points during the life cycle of a B cell.There are only 62 amino acids in CD40 cytoplasmic domain. CD40 could not directly associate of kinases. CD40 transducts the biological signals through tumor necrosis factor receptor- associated proteins (TRAF). TRAFs (TRAF1-6) constitute a family of genetically conserved adapter proteins that has been found in mammals and they have emerged as the major signal transducers for the TNF receptor superfamily. TRAF proteins couple CD40 to the kinase cascade, which finally might activate NF-κB, JNK, receives further support from the demonstration that the cytoplasmic domain sequence, which is required for the binding of TRAF-1, TRAF-2, TRAF-5 and TRAF-6. It has become clear that different TRAFs exhibit specific biological functions. The membrane-proximal events for initiating differential TRAF signal transduction have been relatively well established from the wealth of structural and functional studies. The biggest challenge ahead is to further elucidate the molecular mechanisms of specific TRAF downstream signal transduction by differential TRAF localization and interactions with various intracellular proteins. TRAF2...