Enhanced T-lineage acute lymphoblastic leukaemia cell survival on bone marrow stroma requires involvement of LFA-1 and ICAM-1.
The bone marrow (BM) microenvironment supports leukaemia cell survival and proliferation. The roles played by adhesive receptor interactions in the survival of T-lineage acute lymphoblastic leukaemia (T-ALL) cells on BM stromal cells are not well understood. Recently, we have developed an assay that partially recapitulates the BM microenvironment using HS-5 BM stromal cells. In this assay, the magnitude of ex vivo T-ALL lymphoblast survival predicts patient outcome. We examined the molecular basis for cell-cell adhesive events leading to T-ALL lymphoblast survival on HS-5 and on donor-derived BM stroma. Lympho cyte function-associated antigen-1 (LFA-1) on T-ALL cell lines bound intercellular adhesion molecule-1 (ICAM-1) on HS-5 monolayers, and survival was inhibited 85-98% with monoclonal antibodies directed against LFA-1 or ICAM-1. We compared these results with patient-derived T-ALL lymphoblasts co-cultured on either HS-5 BM or normal BM monolayers and found that LFA-1 and ICAM-1 were required, but not alone sufficient for ex vivo leukaemic cell survival. On normal BM stroma, but not HS-5 monolayers, two additional adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, were highly expressed and contributed to T-ALL cell survival. This is the first report to demonstrate the importance of LFA-1/ICAM-1-mediated adhesion as a critical event in a cascade of cell surface receptor-ligand interactions that regulate T-ALL survival in the BM microenvironment.
Winter
S S
SS
Department of Paediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA. swinter@salud.unm.edu
Sweatman
J J
JJ
Lawrence
M B
MB
Rhoades
T H
TH
Hart
A L
AL
Larson
R S
RS
D017209:Apoptosis; D001854:Bone Marrow Cells / Q000502:physiology*; D002448:Cell Adhesion; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D002648:Child; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000494:pharmacology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000494:pharmacology*; D011485:Protein Binding; D017154:Stromal Cells / Q000502:physiology*
D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1