ARSENIC-INDUCED PML TARGETING ONTO NUCLEAR-BODIES - IMPLICATIONS FOR THE TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA

Acute promyelocytic leukemia (APL) is associated with the t(15;17) tra nslocation, which generates a PML/RAR alpha fusion protein between PML , a growth suppressor localized on nuclear matrix-associated bodies, a nd RAR alpha, a nuclear receptor for retinoic acid (RA). PML/RAR alpha was proposed to block myeloid differentiation through inhibition of n uclear receptor response, as does a dominant negative RAR alpha mutant . In addition, in APL cells, PML/RAR alpha displaces PML and other nuc lear body (NB) antigens onto nuclear microspeckles, likely resulting i n the loss of PML and/or NB functions. RA leads to clinical remissions through induction of terminal differentiation, for which the respecti ve contributions of RAR alpha (or PML/RAR alpha) activation, PML/RAR a lpha degradation, and restoration of NB antigens localiza tion are poo rly determined. Arsenic trioxide also leads to remissions in APL patie nts, 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 target s PML and PML/RAR alpha onto NB and induces their degradation. Thus, R A and arsenic target RAR alpha and PML, respectively, but both induce the degradation of the PML/RAR alpha fusion protein, which should cont ribute to their therapeutic effects. The difference in the cellular ev ents triggered by these two agents likely stems from RA induced transc riptional activation and arsenic effects on NB proteins.