RETINOIC ACID INDUCES AGGREGATION OF THE ACUTE PROMYELOCYTIC LEUKEMIA-CELL LINE NB-4 BY UTILIZATION OF LFA-1 AND ICAM-2

All-trans retinoic acid (tRA) is a potent differentiation agent that i s effective therapy for acute promyelocytic leukemia (APL). However, 5 % to 25% of patients develop retinoic acid syndrome, a potentially lif e-threatening complication in which the pathogenesis relates to adhesi ve alterations of APL cells. Therefore, we investigated the relationsh ip between tRA-induced differentiation and the adhesive properties of APL cells. After confirming differentiation-related morphological chan ges of NB-4 cells in response to tRA, we showed that homotypic aggrega tion 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 neutraliz ing antibodies against LFA-I and ICAM-2. Notably, antibodies directed against VLA-4, other beta(2) integrins [Mac-1 and p150), or other pote ntial LFA-l counterstructures that were expressed on the cell surface (ICAM-1 and ICAM-3) did not block aggregation. Aggregation occurred wi th similar kinetics regardless of the presence of phorbol ester or the ''activating'' monoclonal antibody (MoAb) KIM 185, suggesting that th e 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 syndr ome, MPSS rapidly inhibited homotypic aggregation in a dose-dependent manner. Thus, tRA alters the adhesive properties of APL cells by induc ing the expression of high-avidity beta(2) integrins, aggregation is i nhibited by LFA-1 and ICAM-2 MoAb, and tRA effects are rapidly reversi ble by MPSS. Taken together, our findings provide a clinically relevan t 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 a meliorating retinoic acid syndrome. (C) 1997 by The American Society o f Hematology.