| Abstract: | We have previously reported the presence of monoclonal, tumor-related B lineage cells in the blood of myeloma patients. The cells are continuously differentiating, and the majority are at a very late stage of B cell differentiation into plasma cells, consistent with the hypothesis that they comprise a precursor cell subset responsible for disseminating and possibly for relapse of the disease. The pattern of β1 integrin expression on monoclonal B lineage cells from blood and bone marrow of myeloma patients was evaluated using multiparameter flow cytometry in comparison to normal blood or tissue B cells and malignant B cells from B-CLL, B lymphoma, or plasma cell leukemia. The α4 and β1 chains were found on the majority of normal B cells, usually with a higher expression of α4 compared to β1. α5 was detectable at low density on B cells from lymph node, bone marrow, and lamina propria. The α2 and α6 chains are absent on B cells localized in normal lymphoid tissues as well as on normal blood B cells and in vitro activated B cells. In myeloma, the blood B cells express α2, α5 and α6, suggesting important functional differences between these tumor-related B cells and their normal counterparts. The plasma cells located in myeloma bone marrow express no α2, and almost no α6, although they have variable expression of α4, α5, and β1. Thus the end-stage plasma cells appear to lack receptors that would support a propensity for invasion of basement membranes and exit to extravascular spaces. In contrast, the circulating plasmablasts in a patient with plasma cell leukemia make up a large subset of early plasma cells expressing all integrin receptors analyzed, including α2 and α6. Malignant cells from B-CLL and B lymphoma express only the α4 and β integrins, and some B-CLL have very low levels of α3, but no α2, α5, or α6, suggesting that they may be limited to the vascular spaces and do not extravasate, at least for the stages of disease analyzed here. Our results are therefore consistent with a working hypothesis that invasive capacity in myeloma is to be found within the abnormal monoclonal B cells in peripheral blood, which alone among B cells or plasma cells, and like plasma cell leukemia, express multiple β1 integrins, including the α2 and α6 integrin receptors, necessary for cellular translocation across the endothelial basement membranes and into extravascular spaces. This study raises the possibility that expression of, in particular, the α2 and α6 integrins may underlie the invasiveness of these diseases and offers a new perspective for future avenues of clinical intervention. |
