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The Role of Platelet/Endothelial Cell Adhesion Molecule–1 (CD31) and CD38 Antigens in Marrow Microenvironmental Retention of Acute Myelogenous Leukemia Cells

¹ INSERM ESPRI-EA3855, ² Université François Rabelais, ³ CHRU de Tours, Department of Hematology, Tours, France; ⁴ Cornell University, Weill Medical College, New York, New York; ⁵ University of Torino, Laboratory of Immunogenetics and CeRMS, Turin, Italy; and ⁶ University of Montreal, Institute for Research in Immunology and Cancer, Laboratory of Molecular Genetics of Stem Cells, Montreal, Canada

Requests for reprints: Olivier Herault, Department of Hematology/Institut National de la Sante et de la Recherche Medicale ESPRI-EA3855, University Hospital, 2 bd Tonnelle, F-37044 Tours Cedex, France. Phone: 33-2-4747-4721; Fax: 33-2-4747-6934; E-mail: olivier.herault{at}med.univ-tours.fr.

In acute myelogenous leukemia (AML), leukemic cell-microenvironment interactions within various niches (stromal/osteoblastic or sinusoidal endothelial cell niches) have a role in leukemia cell survival and drug resistance. The AML leukemic cells express platelet/endothelial cell adhesion molecule–1 (CD31) and CD38, two adhesion molecules that could interact with microenvironmental elements, i.e., CD31 on the surface of marrow endothelial cells (CD31/CD31 and CD38/CD31 interactions) and hyaluronate (CD38/hyaluronate interactions). We report a physical association of these two antigens on the plasma membrane of myeloid leukemic cells. In this context, in vitro experiments done using interaction-blocking anti-CD31 and anti-CD38 monoclonal antibodies (CLB-HEC75 and OKT10, respectively) indicate that an excess of CD31 on the cell membrane of leukemic cells (CD31/CD38 MFI ratio >1) promotes a homotypic interaction with marrow endothelial cells, resulting in higher transendothelial migration. Conversely, an excess of CD38 (CD31/CD38 MFI ratio <1) allows leukemic cells to be entrapped within the bone marrow microenvironment through hyaluronate adhesion. The results obtained in vitro using fluorescence resonance energy transfer, co-capping, and co-immunoprecipitation experiments, and hyaluronate adhesion and transendothelial migration assays, are supported by immunophenotypic characterization of marrow leukemic cells from 78 AML patients on which CD38 expression levels were found to be positively correlated with those of CD31. Importantly, the excess of CD31 in those samples was associated with a higher peripheral WBC count. These findings indicate that bone marrow retention of AML cells depends on CD31 and CD38 coexpression levels. [Cancer Res 2007;67(18):8624–32]