PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3.
As(2)O(3) cures acute promyelocytic leukemia (APL) by initiating PML/RARA oncoprotein degradation, through sumoylation of its PML moiety. However, how As(2)O(3) initiates PML sumoylation has remained largely unexplained. As(2)O(3) binds vicinal cysteines and increases reactive oxygen species (ROS) production. We demonstrate that upon As(2)O(3) exposure, PML undergoes ROS-initiated intermolecular disulfide formation and binds arsenic directly. Disulfide-linked PML or PML/RARA multimers form nuclear matrix-associated nuclear bodies (NBs), become sumoylated and are degraded. Hematopoietic progenitors transformed by an As(2)O(3)-binding PML/RARA mutant exhibit defective As(2)O(3) response. Conversely, nonarsenical oxidants elicit PML/RARA multimerization, NB-association, degradation, and leukemia response in vivo, but do not affect PLZF/RARA-driven APLs. Thus, PML oxidation regulates NB-biogenesis, while oxidation-enforced PML/RARA multimerization and direct arsenic-binding cooperate to enforce APL's exquisite As(2)O(3) sensitivity.
Jeanne
Marion
M
Inserm/Centre National de la Recherche Scientifique (CNRS)/Université Paris Diderot/Institut Universitaire Hématologie U944/UMR7212, Laboratoire associé de la Ligue Nationale contre le Cancer, Hôpital St Louis, 1, Av. C. Vellefaux, 75475 Paris, Cedex 10, France.
Lallemand-Breitenbach
Valérie
V
Ferhi
Omar
O
Koken
Marcel
M
Le Bras
Morgane
M
Duffort
Stéphanie
S
Peres
Laurent
L
Berthier
Caroline
C
Soilihi
Hassane
H
Raught
Brian
B
de Thé
Hugues
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004220:Disulfides / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D000071156:Promyelocytic Leukemia Protein; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology
D000970:Antineoplastic Agents; D001152:Arsenicals; D004220:Disulfides; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D046988:Proteasome Endopeptidase Complex; D000077237:Arsenic Trioxide