Arsenic-induced PML targeting onto nuclear bodies: Implications for the treatment of acute promyelocytic leukemia

Arsenic-induced PML targeting onto nuclear bodies: Implications for the treatment of acute promyelocytic leukemia

^*Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197, Rui-Jin Road II, Shanghai 200025, China; and ^†Centre National de la Recherche Scientifique Unité Propre de Recherche 9051, Laboratoire Associé au Comite de Paris de la Ligue contre le Cancer, ^‡Service Clinique des Maladies du Sang, and ^§Service de Biochimie B, Hôpital St. Louis, 1 Avenue Vellefaux, 75475 Paris Cedex 10, France

Abstract

Acute promyelocytic leukemia (APL) is associated with the t(15;17) translocation, which generates a PML/RARα fusion protein between PML, a growth suppressor localized on nuclear matrix-associated bodies, and RARα, a nuclear receptor for retinoic acid (RA). PML/RARα was proposed to block myeloid differentiation through inhibition of nuclear receptor response, as does a dominant negative RARα mutant. In addition, in APL cells, PML/RARα displaces PML and other nuclear body (NB) antigens onto nuclear microspeckles, likely resulting in the loss of PML and/or NB functions. RA leads to clinical remissions through induction of terminal differentiation, for which the respective contributions of RARα (or PML/RARα) activation, PML/RARα degradation, and restoration of NB antigens localization are poorly determined. Arsenic trioxide also leads to remissions in APL patients, presumably through induction of apoptosis. We demonstrate that in non-APL cells, arsenic recruits the nucleoplasmic form of several NB antigens onto NB, but induces the degradation of PML only, identifying a powerful tool to approach NB function. In APL cells, arsenic targets PML and PML/RARα onto NB and induces their degradation. Thus, RA and arsenic target RARα and PML, respectively, but both induce the degradation of the PML/RARα fusion protein, which should contribute to their therapeutic effects. The difference in the cellular events triggered by these two agents likely stems from RA-induced transcriptional activation and arsenic effects on NB proteins.

Footnotes

↵ ¶ To whom reprint requests should be addressed. e-mail: dethe{at}chu-stlouis.fr.
Jean Dausset, Centre d’Étude du Polymorphisme Humain, Paris, France
↵ ‖ This work was presented at the Nobel Symposium on “Functional Organization of the Eukaryotic Cell Nucleus,” held September 3–6, 1996, at Saltsjobaden, Sweden.
ABBREVIATIONS:

APL,

acute promyelocytic leukemia;

NB,

nuclear body;

IFN,

interferon;

RA,

retinoic acid;

RARα,

a nuclear RA receptor