THE PML RETINOIC ACID RECEPTOR-ALPHA TRANSLOCATION CONVERTS THE RECEPTOR FROM AN INHIBITOR TO A RETINOIC ACID-DEPENDENT ACTIVATOR OF TRANSCRIPTION FACTOR-AP-1

We report here that the fusion of PML, a nuclear protein defined by the t(15;17) chromosomal translocation in acute promyelocytic leukemia, with retinoic acid receptor alpha (RARalpha) changes the RARalpha from a retinoic acid (RA)-dependent inhibitor to a RA-dependent activator of AP-1 transcriptional activity. The PML-RARalpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site. Stimulation is dependent on the concentration of RA and its dose-response curve is comparable to that for activation by RARalpha of transcription on RA-responsive genes. Further, in the absence of RA, a circumstance in which RARalpha has no effect on AP-1 activity, PML-RARalpha is an inhibitor. Deletion of the dimerization, transactivation, or DNA-binding domains of c-Jun and removal of the PML dimerization domain in the PML-RARalpha hybrid abrogates their transcriptional cooperativity. In view of the association between AP-1 activity and hemopoietic differentiation, we suggest that these properties of PML-RARalpha could contribute to the leukemic phenotype and its response to RA.