Signal transduction pathways underlying the expression of tissue factor and thrombomodulin in promyelocytic cells induced to differentiate by retinoid acid and dibutyryl cAMP

Acute promyelocytic leukaemia (APL) may be associated with disseminated int ravascular coagulation, as a result of increased tissue factor (TF) express ion and reduced thrombomodulin (TM) expression by APL blast cells. During r etinoid acid (RA)- and dibutyryl cAMP (dbcAMP)-induced differentiation of t he APL cells. there is a marked up-modulation of both the protein kinase A (PKA) and C (PKC) activities. In order to further assess whether these kina ses are intimately associated with both the differentiation process and the regulation of TF and TM expression, we have correlated the modulation of t heir respective pathways with the extent of differentiation and modulation of these cellular receptors, NB4 cells were incubated with all-trans-RA (AT RA) or dbcAMP for up to 48 h. The contribution of phospholipase C (PLC), in ositol phosphate (IP). PKC and PKA in the expression of CD11b. TF and TM wa s studied by the use of specific inhibitors. Myo-inositol uptake and PKC ac tivity increased in cells induced to differentiate by ATRA but the retinoid did not affect cAMP levels or PKA activity. Under treatment with dbcAMP, P KA activity was increased while inositol uptake and PKC activity remained u nchanged. Our results show that the effects of ATRA and dbcAMP on promyeloc ytic cells are closely related. respectively. to the PLC/IP/PKC and the cAM P/PKA pathways. In cells induced to differentiate by ATRA, CD11b expression seems more closely related to inositol uptake than to PKC activity while t he expression of TF and TM show the opposite pattern. which suggests cellul ar events regulated at a different level within a common signal transductio n pathway.