ACCELERATED DEGRADATION OF PML-RETINOIC ACID RECEPTOR-ALPHA (PML-RARA) ONCOPROTEIN BY ALL-TRANS-RETINOIC ACID IN ACUTE PROMYELOCYTIC LEUKEMIA - POSSIBLE ROLE OF THE PROTEASOME PATHWAY

Acute promyelocytic leukemia (APL) is associated with a chromosomal tr anslocation t(15;17) and successfully differentiated by all-trans-reti noic acid (ATRA) in vivo as well as in vitro. The PML-retinoic acid re ceptor cu (RARA) oncoprotein, which is generated by the translocation, blocks the differentiation, and ATRA is thought to modulate the domin ant negative function of PML-RARA. However, the molecular effect of AT RA on PML-RARA is unknown. In this study, we showed by means of immuno blotting that the expression of PML-RARA decreased within 12 h in APL cells treated with ATRA at concentrations greater than 0.1 mu M. The d ecrease of PML-RARA was associated with restoration of the normal subc ellular PML localization. PML-RARA transcripts were not down-regulated by ATRA. However, lactacystin, a specific inhibitor of the proteasome , almost completely inhibited the decrease of PML-RARA. These data ind icate that the PML-RARA degradation is accelerated by pharmacological concentrations of ATRA, suggesting that ATRA allows APL cells to diffe rentiate by relieving the differentiation block.