DIFFERENTIAL USE OF VERY LATE ANTIGEN-4 AND ANTIGEN-5 INTEGRINS BY HEMATOPOIETIC PRECURSORS AND MYELOMA CELLS TO ADHERE TO TRANSFORMING-GROWTH-FACTOR-BETA-1-TREATED BONE-MARROW STROMA

The very late antigen (VLA)-4 and VLA-5 integrins mediate hematopoieti c progenitor cell attachment to bone marrow (BM) stroma, Transforming growth factor-beta (TGF-beta 1) is a cytokine present in the BM microe nvironment that has been shown to regulate the synthesis of adhesion e lements in several cell types. We have investigated whether TGF-beta 1 action on human BM stromal cells affected the adhesion of progenitor cells involving integrins VLA-4 and VLA-5. Two precursor cell lines, p re-B Nalm-6 and the multipotential UT-7, attached to untreated primary stroma and to the human BM stromal cell line Str-5 preferentially usi ng VLA-4, However, treatment of the stroma with TGF-beta 1 resulted in a significant reduction in the participation of VLA-4 in mediating pr ecursor cell adhesion to stroma and a concomitant increase in the util ization of VLA-5. This effect was not exclusive of normal BM stroma, T reatment with TGF-beta 1 of stroma from multiple myeloma BM samples pr oduced a substantial increase in VLA-5 use by the myeloma cell line NC I-H929 to adhere to this stroma. The differential use of VLA-4 and VLA -5 correlated with an increase in fibronectin surface expression by st romal cells in response to TGF-beta 1. Adhesion assays to purified fib ronectin using Nalm-6 cells showed a predominant utilization of VLA-4 at low concentrations of this ligand, whereas higher concentrations re sulted in a preferential use of VLA-5. These results indicate that reg ulation of fibronectin expression on BM stromal cells by TGF-beta 1 re sults in a modulation of the pattern of integrins used by the precurso r and myeloma cells to adhere to BM stroma, which could have important consequences on the proliferation and differentiation of hematopoieti c precursor cells as well as on the localization and growth of myeloma cells.