VASCULAR CELL-ADHESION MOLECULE-1 AND VLA-4 ARE OBLIGATORY ADHESION PROTEINS IN THE HETEROTYPIC ADHERENCE BETWEEN HUMAN LEUKEMIA LYMPHOMA CELLS AND MARROW STROMAL CELLS/

We have utilized two well-characterized human leukemia/lymphoma (LL) c ell lines, UTMB-460 and CEM, to determine the role of integrin very la te antigen-alpha 4 beta(1), (VLA-4) and its ligand vascular cell adhes ion molecule-1 (VCAM-1) in the adherence of the LL cells to marrow str omal cells (MSC). Both these LL cell lines express alpha and beta subu nits of VLA-4. VCAM-1 is constitutively expressed by human MSC and its expression can be upregulated by interleukin-4 (IL-4) and recombinant human tissue necrosis factor-alpha (rTNF-alpha). IL-4 and rTNF-alpha stimulation of MSC is associated with a significant; increase in the a dherence of both UTMB-460 and CEM LL cells to the cytokine-stimulated MSC. Monoclonal antibodies directed against the alpha and beta subunit s of VLA-4 and VCAM-1 significantly inhibit adherence of the LL cells to unstimulated and cytokine-treated MSC. The data reported indicate t hat VCAM-1 and integrin VLA-4 are obligatory adhesion proteins in the heterotypic adherence between human LL cells and MSC. The constitutive expression of VCAM-1 by MSC may be partially responsible for retentio n of leukemia cells in the bone marrow and metastasis of lymphomas to the bone marrow.