Arsenic-induced PML targeting onto nuclear bodies: Implications for the treatment of acute promyelocytic leukemia

DOI Web Site 被引用文献14件
  • Jun Zhu
    Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197, Rui-Jin Road II, Shanghai 200025, China; and Centre National de la Recherche Scientifique Unité Propre de Recherche 9051, Laboratoire Associé au Comite de Paris de la Ligue contre le Cancer, Service Clinique des Maladies du Sang, and Service de Biochimie B, Hôpital St. Louis, 1 Avenue Vellefaux, 75475 Paris Cedex 10, France
  • Marcel H. M. Koken
    Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197, Rui-Jin Road II, Shanghai 200025, China; and Centre National de la Recherche Scientifique Unité Propre de Recherche 9051, Laboratoire Associé au Comite de Paris de la Ligue contre le Cancer, Service Clinique des Maladies du Sang, and Service de Biochimie B, Hôpital St. Louis, 1 Avenue Vellefaux, 75475 Paris Cedex 10, France
  • Frédérique Quignon
    Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197, Rui-Jin Road II, Shanghai 200025, China; and Centre National de la Recherche Scientifique Unité Propre de Recherche 9051, Laboratoire Associé au Comite de Paris de la Ligue contre le Cancer, Service Clinique des Maladies du Sang, and Service de Biochimie B, Hôpital St. Louis, 1 Avenue Vellefaux, 75475 Paris Cedex 10, France
  • Mounira K. Chelbi-Alix
    Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197, Rui-Jin Road II, Shanghai 200025, China; and Centre National de la Recherche Scientifique Unité Propre de Recherche 9051, Laboratoire Associé au Comite de Paris de la Ligue contre le Cancer, Service Clinique des Maladies du Sang, and Service de Biochimie B, Hôpital St. Louis, 1 Avenue Vellefaux, 75475 Paris Cedex 10, France
  • Laurent Degos
    Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197, Rui-Jin Road II, Shanghai 200025, China; and Centre National de la Recherche Scientifique Unité Propre de Recherche 9051, Laboratoire Associé au Comite de Paris de la Ligue contre le Cancer, Service Clinique des Maladies du Sang, and Service de Biochimie B, Hôpital St. Louis, 1 Avenue Vellefaux, 75475 Paris Cedex 10, France
  • Zhen Yi Wang
    Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197, Rui-Jin Road II, Shanghai 200025, China; and Centre National de la Recherche Scientifique Unité Propre de Recherche 9051, Laboratoire Associé au Comite de Paris de la Ligue contre le Cancer, Service Clinique des Maladies du Sang, and Service de Biochimie B, Hôpital St. Louis, 1 Avenue Vellefaux, 75475 Paris Cedex 10, France
  • Zhu Chen
    Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197, Rui-Jin Road II, Shanghai 200025, China; and Centre National de la Recherche Scientifique Unité Propre de Recherche 9051, Laboratoire Associé au Comite de Paris de la Ligue contre le Cancer, Service Clinique des Maladies du Sang, and Service de Biochimie B, Hôpital St. Louis, 1 Avenue Vellefaux, 75475 Paris Cedex 10, France
  • Hugues de Thé
    Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197, Rui-Jin Road II, Shanghai 200025, China; and Centre National de la Recherche Scientifique Unité Propre de Recherche 9051, Laboratoire Associé au Comite de Paris de la Ligue contre le Cancer, Service Clinique des Maladies du Sang, and Service de Biochimie B, Hôpital St. Louis, 1 Avenue Vellefaux, 75475 Paris Cedex 10, France

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<jats:p>Acute promyelocytic leukemia (APL) is associated with the t(15;17) translocation, which generates a PML/RARα fusion protein between PML, a growth suppressor localized on nuclear matrix-associated bodies, and RARα, a nuclear receptor for retinoic acid (RA). PML/RARα was proposed to block myeloid differentiation through inhibition of nuclear receptor response, as does a dominant negative RARα mutant. In addition, in APL cells, PML/RARα displaces PML and other nuclear body (NB) antigens onto nuclear microspeckles, likely resulting in the loss of PML and/or NB functions. RA leads to clinical remissions through induction of terminal differentiation, for which the respective contributions of RARα (or PML/RARα) activation, PML/RARα degradation, and restoration of NB antigens localization are poorly determined. Arsenic trioxide also leads to remissions in APL patients, presumably through induction of apoptosis. We demonstrate that in non-APL cells, arsenic recruits the nucleoplasmic form of several NB antigens onto NB, but induces the degradation of PML only, identifying a powerful tool to approach NB function. In APL cells, arsenic targets PML and PML/RARα onto NB and induces their degradation. Thus, RA and arsenic target RARα and PML, respectively, but both induce the degradation of the PML/RARα fusion protein, which should contribute to their therapeutic effects. The difference in the cellular events triggered by these two agents likely stems from RA-induced transcriptional activation and arsenic effects on NB proteins.</jats:p>

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