ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation.
The human T-cell lymphotropic virus type I (HTLV-1) Tax transactivator initiates transformation in adult T-cell leukemia/lymphoma (ATL), a highly aggressive chemotherapy-resistant malignancy. The arsenic/interferon combination, which triggers degradation of the Tax oncoprotein, selectively induces apoptosis of ATL cell lines and has significant clinical activity in Tax-driven murine ATL or human patients. However, the role of Tax loss in ATL response is disputed, and the molecular mechanisms driving degradation remain elusive. Here we demonstrate that ATL-derived or HTLV-1-transformed cells are dependent on continuous Tax expression, suggesting that Tax degradation underlies clinical responses to the arsenic/interferon combination. The latter enforces promyelocytic leukemia protein (PML) nuclear body (NB) formation and partner protein recruitment. In arsenic/interferon-treated HTLV-1 transformed or ATL cells, Tax is recruited onto NBs and undergoes PML-dependent hyper-sumoylation by small ubiquitin-like modifier (SUMO)2/3 but not SUMO1, ubiquitination by RNF4, and proteasome-dependent degradation. Thus, the arsenic/interferon combination clears ATL through degradation of its Tax driver, and this regimen could have broader therapeutic value by promoting degradation of other pathogenic sumoylated proteins.
Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris Cedex 10, France;
Zeina
Z
Dassouki
Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris Cedex 10, France; INSERM Unité Mixte de Recherche 944, Equipe labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris Cedex 10, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7212, Hôpital St. Louis, Paris Cedex 10, France;
Umut
U
Sahin
Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon;
Hiba
H
El Hajj
Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris Cedex 10, France; INSERM Unité Mixte de Recherche 944, Equipe labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris Cedex 10, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7212, Hôpital St. Louis, Paris Cedex 10, France;
Florence
F
Jollivet
Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon;
Youmna
Y
Kfoury
Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris Cedex 10, France; INSERM Unité Mixte de Recherche 944, Equipe labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris Cedex 10, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7212, Hôpital St. Louis, Paris Cedex 10, France;
Valérie
V
Lallemand-Breitenbach
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Hôpital Necker, Paris Cedex 15, France;
Olivier
O
Hermine
Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris Cedex 10, France; INSERM Unité Mixte de Recherche 944, Equipe labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris Cedex 10, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7212, Hôpital St. Louis, Paris Cedex 10, France; Assistance Publique-Hopitaux de Paris, Service de Biochimie, Hôpital St. Louis, Paris Cedex 10, France; and College de France, Paris, France.
Hugues
H
de Thé
Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon;
Ali
A
Bazarbachi
D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002472:Cell Transformation, Viral / Q000187:drug effects; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016356:Gene Products, tax / Q000378:metabolism*; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D047468:Immunoprecipitation; D007372:Interferons / Q000494:pharmacology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000821:virology*; D009687:Nuclear Proteins / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D059748:Proteolysis / Q000187:drug effects*; D025842:SUMO-1 Protein / Q000378:metabolism*; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D058207:Sumoylation / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
D000998:Antiviral Agents; D001152:Arsenicals; D016356:Gene Products, tax; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C114070:RNF4 protein, human; D025842:SUMO-1 Protein; D013439:Sulfhydryl Reagents; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D007372:Interferons