Mechanisms of action of all-trans-retinoic acid in acute promyelocytic leukaemia

The introduction of all-trans-retinoic acid (RA) in the treatment of acute promyelocytic leukaemia has resulted in a dramatically better outcome for patients suffering from this disease. Extensive studies have been performed over the last few years, aimed to understand the mechanisms by which RA induces its biological effects. All-trans-retinoic acid induces differentiation, cell-cycle arrest and apoptosis of acute promyelocytic leukaemia blasts in vitro and in vivo. It is well established that RA forms complexes with nuclear receptors that bind to specific elements in the promoters of retinoic acid responsive genes, called retinoic acid response elements (RARE), to initiate transcription. Such retinoic acid-dependent gene transcription results in protein-products that ultimately mediate all-trans-retinoic acid-responses. In addition to regulating gene transcription via nuclear receptors, all-trans-retinoic acid induces activation of several cellular pathways in target cells, involving Stat-proteins, Src-family kinases, Crk-proteins and Mitogen-activated protein kinases. This review summarizes the current knowledge on the cellular pathways activated by all-trans-retinoic acid in acute promyelocytic leukaemia cells and on the mechanisms regulating retinoic acid-dependent differentiation and apoptosis.