In acute promyelocytic leukemia (APL) patients, retinoic acid (RA) triggers differentiation while arsenic trioxide (arsenic) induces both a partial differentiation and apoptosis. Although their mechanisms of action are believed to be distinct, these two drugs both induce the catabolism of the oncogenic promyelocytic leukemia (PML)/RARα fusion protein. While APL cell lines resistant to one agent are sensitive to the other, the benefit of combining RA and arsenic in cell culture is controversial, and thus far, no data are available in patients. Using syngenic grafts of leukemic blasts from PML/RARα transgenic mice as a model for APL, we demonstrate that arsenic induces apoptosis and modest differentiation, and prolongs mouse survival. Furthermore, combining arsenic with RA accelerates tumor regression through enhanced differentiation and apoptosis. Although RA or arsenic alone only prolongs survival two- to threefold, associating the two drugs leads to tumor clearance after a 9-mo relapse-free period. These studies establishing RA/arsenic synergy in vivo prompt the use of combined arsenic/RA treatments in APL patients and exemplify how mouse models of human leukemia can be used to design or optimize therapies.
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5 April 1999
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April 05 1999
Retinoic Acid and Arsenic Synergize to Eradicate Leukemic Cells in a Mouse Model of Acute Promyelocytic Leukemia
Valérie Lallemand-Breitenbach,
Valérie Lallemand-Breitenbach
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
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Marie-Claude Guillemin,
Marie-Claude Guillemin
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
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Anne Janin,
Anne Janin
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
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Marie-Thérèse Daniel,
Marie-Thérèse Daniel
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
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Laurent Degos,
Laurent Degos
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
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Scott C. Kogan,
Scott C. Kogan
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
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J. Michael Bishop,
J. Michael Bishop
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
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Hugues de Thé
Hugues de Thé
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
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Valérie Lallemand-Breitenbach
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
Marie-Claude Guillemin
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
Anne Janin
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
Marie-Thérèse Daniel
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
Laurent Degos
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
Scott C. Kogan
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
J. Michael Bishop
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
Hugues de Thé
From the *Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; ‡Service d'Anatomie Pathologique, §Service d'Hématologie Biologique, ‖Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ¶The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552
Address correspondence to Hugues de Thé, Centre National de la Recherche Scientifique, UPR 9051, Institut d'Hématologie, Hôpital St. Louis, 1, Av. C. Vellefaux 75475 Paris, Cedex 10 France. Phone: 33-1-53-72-21-91; Fax: 33-1-53-72-21-90; E-mail: [email protected]
We warmly thank all members of the PML group for suggestions during the course of this work and for critical reading of the manuscript. We thank Prof. Zhu Chen (Shanghai Institute of Hematology, Rui-Jin Hospital, China) for sharing unpublished results and constructive discussions at various stages of this work. We are grateful to M. Pla and her team, as well as to J. Valla for help in the animal facilities. We thank B. Cassina and C. Chomienne for PCR analysis, and S. Chevret for statistical analysis. Laboratoire Photo Hematologie is acknowledged for the artwork, and the Department of Pathology and Electron Microscopy for their efficient cooperation.
This project was supported by grants from Ligue contre le Cancer (Nationale and Comité de Paris), Association pour la Recherche contre le Cancer (ARC), European Economic Community (EEC; BIOMED II), Fondation St. Louis, and the University of Paris VII.
Received:
October 27 1998
Revision Received:
January 18 1999
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1999
J Exp Med (1999) 189 (7): 1043–1052.
Article history
Received:
October 27 1998
Revision Received:
January 18 1999
Citation
Valérie Lallemand-Breitenbach, Marie-Claude Guillemin, Anne Janin, Marie-Thérèse Daniel, Laurent Degos, Scott C. Kogan, J. Michael Bishop, Hugues de Thé; Retinoic Acid and Arsenic Synergize to Eradicate Leukemic Cells in a Mouse Model of Acute Promyelocytic Leukemia . J Exp Med 5 April 1999; 189 (7): 1043–1052. doi: https://doi.org/10.1084/jem.189.7.1043
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