Tissue factors on acute promyelocytic leukemia and endothelial cells are differently regulated by retinoic acid, arsenic trioxide and chemotherapeutic agents

The aberrant expression of tissue factor (TF) in acute promyelocytic leukemia (APL) cells has been implicated in the pathogenesis of the APL coagulopathy. In this study, we found that in APL patients receiving ATRA or As2O3 treatment, the improvement in hypercoagulobility and hyperfibrinolysis paralleled the correction of plasma fibrinogen level and amelioration of bleeding symptoms. Notably, clinical improvement was also correlated to ATRA/As2O3-induced rapid decrease of membrane procoagulant activity (PCA) and TF contents of APL blasts. Consistent with the in vivo findings, the membrane PCA, TF antigen and its mRNA level within NB4 cells were rapidly down-regulated by 1 microM ATRA or As2O3, while 0.2 microg/ml DNR increased these TF parameters prior to its effect upon apoptosis induction. The down-regulation of TF mRNA by ATRA was partially de novo protein synthesis-dependent and at least partially attributed to a mechanism of destabilizing TF mRNA. On the other hand, in addition to its modulation on mRNA, As2O3 could also induce an accelerated TF protein turnover. These distinct effects were corroborated with the properties of these agents in causing the degradation of PML-RARalpha protein. All three therapeutic agents, however, enhanced the potential of NB4 cells to stimulate the expression of TF and PCA in endothelium. Taken together, our data suggest that the rapid and distinct regulation of TF on APL cells by these therapeutic agents might at least partially contribute to their effects on APL coagulopathy.