ALL-TRANS-RETINOIC ACID INCREASES ADHESION TO ENDOTHELIUM OF THE HUMAN PROMYELOCYTIC LEUKEMIA-CELL LINE NB4

Pulmonary distress symptoms and thrombotic complications are side-effe cts of all-trans-retinoic acid (ATRA) therapy for remission induction in acute promyelocytic leukaemia (APL). The ATRA-induced increase of l eukaemic cell adhesive molecules may be responsible. To explore this w e used a functional assay to study the effect of ATRA treatment on the adhesion of blast cells to cultured human endothelial cells (EC), end othelial cell matrix (ECM), and interleukin 1 beta-activated EC (IL1 EC). NB4 cells, a maturation-inducible human promyelocytic leukaemia cell line, were treated with 1 mu M ATRA or the vehicle (control), lab elled with Cr-51 and tested in the adhesion assay. ATRA increased NB4 adhesion to EC (P < 0.01), ECM (P < 0.001) and IL1 + EC (P = n.s.). An inhibition study with anti-EC adhesion receptors MoAbs indicated that anti-E-selectin, anti-VCAM-1 and anti-ICAM-1 effectively inhibited ce ll adhesion to IL1 + EC (18 +/- 7%, 45 +/- 6.9% and 29 +/- 6% inhibiti on, respectively) and to unstimulated EC. Preincubation of ATRA-treate d NB4 cells with MoAbs anti-VLA4 and anti-LFA1, the VCAM-1 and ICAM-1 counterreceptors respectively, resulted in a significant inhibition of adhesion. Cytofluorimetric analysis of the NB4 cell membrane molecule s confirmed the increase under ATRA of VLA4, LFA1, MAC1 and ICAM-1, Th erefore ATRA increases NB4 cell adhesion to the endothelium and the su bendothelial matrix. These findings parallel the increment of NB4 surf ace adhesive molecules, among which VLA4 and LFA1 appear to play an im portant part, These mechanisms may contribute to the complications of ATRA therapy in APL.