MOLECULAR-INTERACTIONS BETWEEN HUMAN B-CELL PROGENITORS AND THE BONE-MARROW MICROENVIRONMENT

Apoptosis of normal and leukemic immature B-cells in vitro is suppress ed when either cell type is grown in direct contact with a feeder laye r of bone marrow-derived stromal cells, including fibroblasts, macroph ages, endothelial cells, and adipocytes. In this study, our objective was to identify a stromal cell type which is essential for lymphoblast survival and to characterize the molecules involved in lymphoblast ad hesion to these cells. In experiments with B-lineage acute lymphoblast ic leukemia (ALL) cells (n = 28) and purified CD19(+) cells from norma l bone marrow (n = 6) we found that homogeneous populations of bone ma rrow fibroblasts could sustain survival of normal and leukemic immatur e B-cells as efficiently as composite bone marrow stromal layers. Elec tron microscopic studies showed that leukemic lymphoblasts associate w ith fibroblasts and with the extracellular matrix (ECM) primarily via their specialized cell surface structures. Immunogold labeling/electro n microscopy analysis revealed that the areas of contact between lymph oblasts and fibroblasts contained beta 1 integrins (VLA-4 and VLA-B), fibronectin, vascular cell adhesion molecule (VCAM-1), and a cartilage -link protein, CD44. Double immunogold labeling studies disclosed a di rect in situ relationship between fibronectin and VLA-4, VLA-B, and CD 44. We hypothesize that these molecular interactions either bring lymp hoblasts into close physical proximity with other fibroblast-bound or ECM-bound survival factors or provide survival signals themselves. (C) 1996 Academic Press, Inc.