THE PML AND PML RAR-ALPHA DOMAINS - FROM AUTOIMMUNITY TO MOLECULAR ONCOLOGY AND FROM RETINOIC ACID TO ARSENIC/

Acute promyelocytic leukemia (APL) is specifically associated to a t(1 5;17) translocation which fuses a gene encoding a nuclear receptor for retinoic acid, RAR alpha, to a previously unknown gene PML. The PML p rotein is localized in the nucleus on a specific domain of unknown fun ction (PML nuclear bodies, NB) previously detected with autoimmune ser a from patients with primary biliary cirrhosis (PBC). These bodies are nuclear matrix-associated and all of their identified components (PML , Sp100, and NDP52) are sharply upregulated by interferons. We show th at autoantibodies against both PML and Sp100 are usually associated in sera with multiple nuclear dot anti-nuclear antibodies and demonstrat e that PML is an autoantigen, not only in PBC, but also in other autoi mmune diseases. In APL, the PML/RAR alpha fusion interferes with both the retinoic acid (RA) response and PML localization on nuclear bodies , but the respective contribution of each defect to leukemogenesis is unclear. RA induces the terminal differentiation of APL blasts, yieldi ng to complete remissions, and corrects the localization of NB antigen s, Arsenic trioxide (As2O3) also induces remissions in APL, seemingly through induction of apoptosis. We show that in APL, As2O3 leads to th e rapid reformation of PML bodies. Thus, both agents correct the defec t in NB antigen localization, stressing the role of nuclear bodies in the pathogenesis of APL. (C) 1996 Academic Press, Inc.