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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4308-4316
Trivalent Antimonials Induce Degradation of the PML-RAR
Oncoprotein and Reorganization of the Promyelocytic Leukemia
Nuclear Bodies in Acute Promyelocytic Leukemia NB4 Cells
Stefan Müller,
Wilson H. Miller Jr, and
Anne Dejean
From the Unité de Recombinaison et Expression
Génétique, INSERM U 163, Institut Pasteur, Paris, France;
and the Lady Davis Institute for Medical Research, McGill University,
Montreal, Canada.
Acute promyelocytic leukemia (APL) is characterized by a specific
t(15;17) chromosomal translocation that fuses the genes encoding the
promyelocytic leukemia protein (PML) and the retinoic acid receptor 
(RAR). The resulting PML-RAR protein induces a block in the
differentiation of the myeloid progenitor cells, which can be released
by retinoic acid (RA) in vitro and in vivo. The RA-induced
differentiation of APL blasts is paralleled by the degradation of the
fusion protein and the relocation of wild-type PML from aberrant
nuclear structures to its normal localization in nuclear bodies.
Recently, arsenic trioxide (As2O3) treatment was proposed as an alternative therapy in APL, because it can induce
complete remission in both RA-sensitive and -resistant APL patients.
Intriguingly, As2O3 was also shown to induce
degradation of the PML-RAR chimera and to reorganize PML nuclear
bodies. Here we show that trivalent antimonials also have striking
effects on RA-sensitive and RA-resistant APL cells. Treatment of the
APL-derived NB4 cells and the RA-resistant subclone NB4R4 with antimony
trioxide or potassium antimonyl tartrat triggers the degradation of the fusion protein and the concomitant reorganization of the PML nuclear bodies. In addition, as reported for As2O3, the
antimonials provoke apoptosis of NB4 and NB4R4 cells. The mechanism of
antimony action is likely 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. From these data, we propose that, in analogy to
As2O3, antimonials might have a beneficial
therapeutic effect on APL patients, perhaps with less toxicity than
arsenic.
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