TRIVALENT ANTIMONIALS INDUCE DEGRADATION OF THE PML-RAR-ALPHA ONCOPROTEIN AND REORGANIZATION OF THE PROMYELOCYTIC LEUKEMIA NUCLEAR-BODIES IN ACUTE PROMYELOCYTIC LEUKEMIA NB4 CELLS

Acute promyelocytic leukemia (APL) is characterized by a specific t(15 ;17) chromosomal translocation that fuses the genes encoding the promy elocytic leukemia protein (PML) and the retinoic acid receptor alpha ( RAR alpha). the resulting PML-RAR alpha protein induces a block in the differentiation of the myeloid progenitor cells, which can be release d by retinoic acid (RA) in vitro and in vivo. The RA-induced different iation of APL blasts is paralleled by the degradation of the fusion pr otein and the relocation of wild-type PML from aberrant nuclear struct ures to its normal localization in nuclear bodies. Recently, arsenic t rioxide (As2O3) treatment was proposed as an alternative therapy in AP L, because it can induce complete remission in both HA-sensitive and - resistant APL patients. Intriguingly, As2O3 was also shown to induce d egradation of the PML-RAR alpha chimera and to reorganize PML nuclear bodies. Here we show that trivalent antimonials also have striking eff ects on RA-sensitive and RA-resistant APL cells. Treatment of the APL- derived NB4 cells and the RA-resistant subclone NB4R4 with antimony tr ioxide or potassium antimonyl tartrat triggers the degradation of the fusion protein and the concomitant reorganization of the PML nuclear b odies. In addition, as reported for As2O3, the antimonials provoke apo ptosis of NB4 and NB4R4 cells. The mechanism of antimony action is lik ely to be similar to that of As2O3, notably both substances induce the attachment of the ubiquitin-like SUMO-1 molecule to the PML moiety of PML-RAR alpha. From these data, we propose that, in analogy to As2O3, antimonials might have a beneficial therapeutic effect on APL patient s, perhaps with less toxicity than arsenic. (C) 1998 by The American S ociety of Hematology.