EXPRESSION OF MULTIPLE BETA-1 INTEGRINS ON CIRCULATING MONOCLONAL-B CELLS IN PATIENTS WITH MULTIPLE-MYELOMA

We have previously reported the presence of monoclonal, tumor-related B lineage cells in the blood of myeloma patients. The cells are contin uously differentiating, and the majority are at a very late stage of B cell differentiation into plasma cells, consistent with the hypothesi s that they comprise a precursor cell subset responsible for dissemina ting and possibly for relapse of the disease. The pattern of beta1 int egrin expression on monoclonal B lineage cells from blood and bone mar row of myeloma patients was evaluated using multiparameter flow cytome try in comparison to normal blood or tissue B cells and malignant B ce lls from B-CLL, B lymphoma, or plasma cell leukemia. The alpha4 and be ta1 chains were found on the majority of normal B cells, usually with a higher expression of alpha4 compared to beta1. Alpha5 was detectable at low density on B cells from lymph node, bone marrow, and lamina pr opria. The alpha2 and alpha6 chains are absent on B cells localized in normal lymphoid tissues as well as on normal blood B cells and in vit ro activated B cells. In myeloma, the blood B cells express alpha2, al pha5, and alpha6, suggesting important functional differences between these tumor-related B cells and their normal counterparts. The plasma cells located in myeloma bone marrow express no alpha2, and almost no alpha6, although they have variable expression of alpha4, alpha5, and beta1. Thus the end-stage plasma cells appear to lack receptors that w ould 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 pl asma cells expressing all integrin receptors analyzed, including alpha 2 and alpha6. Malignant cells from B-CLL and B lymphoma express only t he alpha4 and beta1 integrins, and some B-CLL have very low levels of alpha3, but no alpha2, alpha5, or alpha6, suggesting that they may be limited to the vascular spaces and do not extravasate, at least for th e stages of disease analyzed here. Our results are therefore consisten t with a working hypothesis that invasive capacity in myeloma is to be found within the abnormal monoclonal B cells in peripheral blood, whi ch alone among B cells or plasma cells, and like plasma cell leukemia, express multiple beta1 integrins, including the alpha2 and alpha6 int egrin receptors, necessary for cellular translocation across the endot helial basement membranes and into extravascular spaces. This study ra ises the possibility that expression of, in particular, the alpha2 and alpha6 integrins may underlie the invasiveness of these diseases and offers a new perspective for future avenues of clinical intervention.