INTERFERONS AND RETINOIDS ENHANCE AND DEXAMETHASONE SUPPRESSES UROKINASE-MEDIATED PLASMINOGEN ACTIVATION IN PROMYELOCYTIC LEUKEMIA-CELLS

All-trans retinoic acid (RA) has been successfully used in the treatme nt of patients with acute promyelocytic leukemia (APL). It induces dif ferentiation of APL cells and reduces the bleeding tendency in APL pat ients. It has been proposed that plasminogen activation could affect t he fibrinolytic balance in patients with leukemia. In our earlier stud y we found that treatment of APL cells with RA results in changes in u rokinase (uPA) production. As interferons (IFNs) and dexamethasone can be used together with RE in the treatment of patients with APL, we ha ve now studied the effects of RA together with IFNs and dexamethasone an the plasminogen activation cascade of these cells, including measur ement of plasmin generation and uPA receptor (uPAR), using enzyme immu noassays, fluorescence-activated cell sorter analysis and RNA extracti on with Northern blotting. Our main results were: (1) plasmin was form ed on the surface of APL cells; (2) RA stimulated transiently plasmin generation and increased uPAR mRNA level; (3) IFNs alpha and gamma pot entiated RA in its effects on uPA and plasmin activities and on uPAR l evel; (4) dexamethasone suppressed totally the effect of RA on uPA ind uction and plasminogen activation; and (5) IFNs and dexamethasone alon e did nor have potent effects on plasminogen activation. These results may assist in the design of therapy for APL patients.