Selective Homing of Human Leukemic B-Cell Precursors to Specific Lymphohematopoietic Microenvironments in SCID Mice: A Role for the β 1 Integrin Family Surface Adhesion Molecules VLA-4 and VLA-5

Abstract

We used a SCID mouse xenograft model to study the in vivo growth patterns of primary leukemic cells from six patients with newly diagnosed B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), including two patients with t(1; 19) ALL, two patients with t(4; 11) ALL, and two patients with t(9;22) ALL. Leukemic cells from these six patients caused overt leukemia in SCID mice with extensive multiple organ involvement. Leukemic BCP from SCID mice xenografted with leukemic cells from two t(9;22) ALL patients expressed very high levels of both VLA-4 and VLA-5 regardless of the tissue of origin. By comparison, in SCID mice xenografted with leukemic cells two patients with t(1; 19) ALL and two patients with t(4; 11) ALL, leukemic BCP bone marrow samples expressed high levels of VLA-4 as well as VLA-5, whereas the vast majority of leukemic BCP in the liver or spleen samples expressed neither of these adhesion molecules at significant levels. These results suggest that the expression of VLA-4 and VLA-5 on t(1;19) or t(4;11) leukemia cells likely determines their binding capacity to bone marrow stroma and may affect their migration to extramedullary tissues. Our findings are in accord with and extend previous studies which demonstrated that extracellular matrix and integrins influence development, compartmentalization, and migration of BCP during B-cell ontogeny. The described SCID mouse model system provides a unique opportunity to study the adhesion receptors which regulate the selective homing of human leukemic BCP to specific SCID mouse organs.