All‐trans retinoic acid regulates adhesion mechanism and transmigration of the acute promyelocytic leukaemia cell line NB‐4 under physiologic flow

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Abstract
The success of all‐trans retinoic acid (ATRA) in the therapy of acute promyelocytic leukaemia (APL) has received increased attention. Unfortunately, life‐threatening multiorgan failure commonly occurs, i.e. retinoic acid syndrome, and is thought to be the result of organ infiltration by leukaemic cells. We hypothesized that ATRA‐induced differentiation of APL cells leads to adhesion receptor alterations responsible for leucocyte extravasation from the blood into tissue. Changes in adhesive properties of the APL cell line NB‐4 in response to ATRA were investigated using a parallel plate flow chamber under conditions that recapitulate physiologic flow conditions. Untreated NB‐4 cells initially tether and roll on activated human umbilical vein endothelial cell monolayers using a combination of E‐selectin, P‐selectin and α4 integrin. After ATRA treatment, > 80% of initial NB‐4 cell attachment to endothelial cells was E‐selectin dependent. Stable arrest (firm adherence) of NB‐4 cells on activated endothelium was also altered by ATRA treatment. Untreated NB‐4 cells used α4 integrin to arrest on endothelium, but β2 integrin dependent arrest was induced by ATRA. With the acquisition of β2 integrin function, ATRA‐treated cells acquired the ability to transmigrate through activated endothelium. Thus, ATRA dramatically altered the adhesion phenotype on NB‐4 cells: ATRA induced rolling largely attributable to E‐selectin, abrogated α4 integrin dependent rolling, and promoted acquisition of β2 integrin dependent firm adherence and transmigration. These findings represent novel cellular and differentiation effects of ATRA, and, to our knowledge, are the first demonstration that a therapeutic agent differentially regulates α4 and β2 integrin on the same leucocyte.