AII-trans retinoic acid (RA) represents a major advance that has made acute promyelocytic leukemia (APL) the most curable subtype of acute myeloid leukemia in adults. Although, RA's overall toxicity is considerably less compared to the standard toxic chemotherapy, its use has been associated with the development of a potentially fatal condition called, RA syndrome. The only drug available for preventing RA syndrome is the high dose of dexamethasone, even though its mechanism of action is not understood. The pathogenesis of RA syndrome and management remains to be the challenge for the present. The syndrome is typical of APL patients; it neither occurs in individuals taking RA for other reasons nor the APL patients treated with chemotherapy alone develop this condition. More specifically, the syndrome has not been observed in APL patients receiving RA during complete remission. Based on these observations, it is postulated that RA syndrome may represents a secondary event related to the aberrant interaction between differentiating myeloid cells and host tissues. Based on our initial observations that: a) RA-is a potent inducer of cell-surface CD38 antigen expression in APL cells; b) CD38 antigen can serve as a receptor and its ligation can induce potent growth-stimulatory and inflammatory signals; and c) human lung endothelial cells express a cell-surface protein that can serve as a putative CD38 ligand; we propose that RA-induced CD38 antigen may play a central role in the development of RA syndrome pathogenesis. Thus, RA-induced CD38 antigen may result in an increased adherence between CD38-positive maturing APL cells and the endothelium of lung capillaries. This initial step may generate the congestive clinical picture and induce (or may determine) an uncontrolled cytokine release. The studies proposed in this grant application will address in depth the involvement of CD38 antigen in promoting the adhesion of RA-induced APL cells to lung endothelial cells and consequence and contribution of such interaction in the development of RA syndrome. By accomplishing the stated aims, we hope to define the molecular mechanisms involved in the pathogenesis of RA syndrome, the knowledge that will help design better approaches to control this potentially fatal condition. ? ?
Showing the most recent 10 out of 12 publications
