The PML and PML/RARalpha domains: from autoimmunity to molecular oncology and from retinoic acid to arsenic.
Acute promyelocytic leukemia (APL) is specifically associated to a t(15; 17) translocation which fuses a gene encoding a nuclear receptor for retinoic acid, RARalpha, 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/RARalpha 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 (As2O3) 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.
Andre
C
C
Service d'Immunologie Biologique and Service d'hépatologie et Gastro-entérologie, CHU Henri Mondor, Creteil Cedex, 94010, France.
Guillemin
M C
MC
Zhu
J
J
Koken
M H
MH
Quignon
F
F
Herve
L
L
Chelbi-Alix
M K
MK
Dhumeaux
D
D
Wang
Z Y
ZY
Degos
L
L
Chen
Z
Z
de The
H
H
D000818:Animals; D000974:Antibodies, Antinuclear; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D001324:Autoantigens; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000235:genetics*; D016466:CHO Cells; D002454:Cell Differentiation / Q000187:drug effects; D006224:Cricetinae; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000276:immunology; D010087:Oxides / Q000494:pharmacology; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D000974:Antibodies, Antinuclear; D000970:Antineoplastic Agents; D001152:Arsenicals; D001324:Autoantigens; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070576:PML protein, human; D014212:Tretinoin; D000077237:Arsenic Trioxide