title: Retinoic acid induces aggregation of the acute promyelocytic leukemia cell line NB-4 by utilization of LFA-1 and ICAM-2.
abstract: All-trans retinoic acid (tRA) is a potent differentiation agent that is effective therapy for acute promyelocytic leukemia (APL). However, 5% to 25% of patients develop retinoic acid syndrome, a potentially life-threatening complication in which the pathogenesis relates to adhesive alterations of APL cells. Therefore, we investigated the relationship between tRA-induced differentiation and the adhesive properties of APL cells. After confirming differentiation-related morphological changes of NB-4 cells in response to tRA, we showed that homotypic aggregation of NB-4 cells grown in tRA for 72 hours is dose-dependent with a median effective dose of approximately 50 nmol/L. Maximal aggregation occurred at mean and peak therapeutic serum concentrations (100 and 1,000 nmol/L, respectively). Aggregation also increased with the length of tRA exposure over 168 hours. Aggregation was inhibited by neutralizing antibodies against LFA-1 and ICAM-2. Notably, antibodies directed against VLA-4, other beta2 integrins (Mac-1 and p150), or other potential LFA-1 counterstructures that were expressed on the cell surface (ICAM-1 and ICAM-3) did not block aggregation. Aggregation occurred with similar kinetics regardless of the presence of phorbol ester or the "activating" monoclonal antibody (MoAb) KIM 185, suggesting that the avidity of LFA-1 is not modulated on NB-4 cells in a manner similar to other leukocytes. Consistent with the prompt clinical effectiveness of methyl prednisolone sodium succinate (MPSS) in retinoic acid syndrome, MPSS rapidly inhibited homotypic aggregation in a dose-dependent manner. Thus, tRA alters the adhesive properties of APL cells by inducing the expression of high-avidity beta2 integrins, aggregation is inhibited by LFA-1 and ICAM-2 MoAb, and tRA effects are rapidly reversible by MPSS. Taken together, our findings provide a clinically relevant system for study of LFA-1/ICAM-2 interaction and suggest a mechanism in part for retinoic acid syndrome and the effectiveness of MPSS in ameliorating retinoic acid syndrome.
authors.affiliation: Department of Pathology, University of New Mexico Cancer Center, Albuquerque 87131-5636, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Larson
authors.forename: D C
authors.initials: DC
authors.lastname: Brown
authors.forename: L A
authors.initials: LA
authors.lastname: Sklar
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000502:physiology*; D002449:Cell Aggregation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D004492:Edetic Acid / Q000494:pharmacology; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000502:physiology*; D008776:Methylprednisolone Hemisuccinate / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects*; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014212:Tretinoin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; C065289:ICAM2 protein, human; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D009363:Neoplasm Proteins; D016201:Receptors, Lymphocyte Homing; D014212:Tretinoin; D008776:Methylprednisolone Hemisuccinate; D004492:Edetic Acid; D013755:Tetradecanoylphorbol Acetate