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The PML and PML/RAR alpha Domains: From Autoimmunity to Molecular Oncology and from Retinoic Acid to Arsenic

CHANTAL ANDRE,* MARIE-CLAUDE GUILLEMIN,1 JUN ZHU,2 MARCEL H. M. KOKEN,1 FRÉDÉRIQUE QUIGNON,1 LAURENCE HERVE,* MOUNIRA K. CHELBI-ALIX,1 DANIEL DHUMEAUX,* ZENG-YI WANG,2 LAURENT DEGOS,1 ZHU CHEN,2 AND HUGUES DE THE1
*Service d'lmmunologie Biologique and SerVice d'hépatologie et Gastro-entérologie, CHU Henri Mondor, 94010 Creteil Cedex, France; 1CNRS UPR 9051, Service des Maladies du Sang and Service de Biochimie, Hôpital St. Louis, 75475 Paris Cedex 10, France; and 2Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197, Rui-Jin Road 11, Shanghai 200025, China




Abstract
Acute promyelocytic leukemia (APL) is specifically associated to a t(15; 17) translocation which fuses a gene encoding a nuclear receptor for retinoic acid, RAR alpha, to a previously unknown gene PML. The PML protein is localized in the nucleus on a specific domain of unknown function (PML nuclear bodies, NB) previously detected with autoimmune sera 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 that autoantibodies against both PML and Sp100 are usually associated in sera with multiple nuclear dot anti-nuclear antibodies and demonstrate that PML is an autoantigen, not only in PBC, but also in other autoimmune diseases. In APL, the PML/12RAR 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, yielding to complete remissions, and corrects the localization of NB antigens. Arsenic trioxide (As203) also induces remissions in APL, seemingly through induction of apoptosis. We show that in APL, As2O3 leads to the rapid reformation of PML bodies. Thus, both agents correct the defect in NB antigen localization, stressing the role of nuclear bodies in the pathogenesis of APL.

EXPERIMENTAL CELL RESEARCH 229
253 - 260 (1996)
ARTICLE NO. 0368
Copyright © 1996 Academic Press, Inc.

 

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