Roles of CD19 Molecules That Suppress Proliferation and Induce Apoptosis in Human Myeloma Cells.

CD19 is a B cell-specific membrane protein belonging to immunoglobulin superfamily, and acts as a positive or negative regulator in B cell signaling. Although plasma cells still express CD19, CD19 expression is lost in malignant plasma cells with the progression of multiple myeloma (MM) including monoclonal gammopathy of undermined significance (MGUS). To understand the pathological significance of loss of CD19 in human myelomas, we examined the biological effect of CD19 expression on myeloma cells by generating CD19 transfectants of a myeloma cell line, U266. CD19 transfectants showed slower growth rate in vitro than controls, such as mock and ΔCD19 transected with a truncated form of CD19. The growth-inhibitory effect was CD19-specific and presumably due to the intracellular signaling events via CD19 because this effect was not observed in ΔCD19. Furthermore, serum withdrawal rapidly induced the apoptosis of the CD19-transfectants that was rescued by insulin-like growth factor (IGF-I) as compared with CD19⁻ controls. These may suggest that the CD19 transfectants are likely to be dependent on the growth factors, such as IGF-I, to survive and proliferate, and thus, susceptible to the serum deprivation-induced apoptosis. IGF-I activates extracellular signal-regulated kinase (ERK) 1/2 and phosphatidylinositol-3-kinase (PI-3K) that are important for proliferation of myeloma cells. Western bolt analysis showed that IGF-1-induced activation of ERK1/2 was reduced in the CD19 transfectants, although the similar levels of IGF-I receptors were expressed in the CD19 transfectants and CD19⁻ controls. In contract, CD19 failed to inhibit the IGF-I-mediated PI-3K/AKT activation, whereas a downstream target in the PI-3K pathway, p70S6 kinase activation was decreased in the CD19 transfectants. However, the p70S6 kinase activity could be influenced by both ERK1/2 and PI-3K pathways after IGF-1 stimulation, and the MAPK pathway seems to be a major regulator for myeloma cell growth. Our results, therefore, suggest that the recovering expression of CD19 molecules and genes in human myeloma cells may be an important consideration in therapeutic approaches in human MM.