Key differentiation steps in normal B cells and in myeloma cells

The malignant plasma cell in multiple myeloma expresses a monoclonal immunoglobulin (Ig) with a somatically mutated variable region. In humans, somatic hypermutation of Ig variable regions only occurs in mature B cells, during the helper T-cell (TH)-dependent germinal center (GC) reaction. Within this context, the major differentiation steps in normal B cells will be discussed: B-cell maturation, B-cell activation, the GC reaction--during which the B cells strongly proliferate and somatic hypermutation in conjunction with stringent cell selection leads to antibody affinity maturation--and the differentiation of B cells into plasma cells or memory cells. The myeloma cell resembles a normal plasma cell with regard to many of its biologic features, such as its homing to the bone marrow, interaction with stromal cells, or even its capacity to suppress hematopoiesis. While the expression of interleukin-6 (IL-6) and IL-10 disappears during normal differentiation of B cells into plasma cells, that of transforming growth factor beta 1 persists. Thus, normal plasma cells in principle could, like myeloma cells, suppress hematopoiesis if their proportion in the bone marrow greatly increased (this could occur, for example, in bone marrow aplasia). The specific key alteration leading to multiple myeloma still remains to be identified.