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Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation

Nature Medicine volume 14, pages 1333–1342 (2008)Cite this article

A Corrigendum to this article was published on 01 January 2009

Abstract

Retinoic acid and arsenic trioxide target the protein stability and transcriptional repression activity of the fusion oncoprotein PML-RARA, resulting in regression of acute promyelocytic leukemia (APL). Phenotypically, retinoic acid induces differentiation of APL cells. Here we show that retinoic acid also triggers growth arrest of leukemia-initiating cells (LICs) ex vivo and their clearance in PML-RARA mouse APL in vivo. Retinoic acid treatment of mouse APLs expressing the fusion protein PLZF-RARA triggers full differentiation, but not LIC loss or disease remission, establishing that differentiation and LIC loss can be uncoupled. Although retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation. A cyclic AMP (cAMP)-dependent phosphorylation site in PML-RARA is crucial for retinoic acid–induced PML-RARA degradation and LIC clearance. Moreover, activation of cAMP signaling enhances LIC loss by retinoic acid, identifying cAMP as another potential APL therapy. Thus, whereas transcriptional activation of PML-RARA is likely to control differentiation, its catabolism triggers LIC eradication and long-term remission of mouse APL. Therapy-triggered degradation of oncoproteins could be a general strategy to eradicate cancer stem cells.

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Figure 1: Retinoic acid (RA) triggers APL cell differentiation and loss of clonogenic precursors ex vivo and in vivo.
Figure 2: Full differentiation without APL clearance in PLZF-RARA APL or PML-RARA APL treated with low-dose retinoic acid (RA).
Figure 3: LIC eradication by retinoic acid (RA) and arsenic depends on active proteolysis.
Figure 4: Activation of cAMP signaling synergizes with low-dose retinoic acid (RA) to induce LIC loss in wild-type PML-RARA but not in RA-resistant PML-RARAL902P APL.
Figure 5: Loss of the Ser873 PKA phosphorylation site in PML-RARA results in retinoic acid (RA)-resistant APLs.
Figure 6: PKA phosphorylation site in RARA and PML-RARA is dispensable for retinoic acid (RA)-induced activation of target genes but desensitizes PML-RARA to RA-induced degradation.

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Acknowledgements

R.N. was supported by the Lady Tata Foundation (London). This work was supported by the ARECA, EPITRON (an integrated project funded by the European Union under the sixth framework program (LSHC-CT-2005-518417)) and INCa/Canceropole programs. We thank J. Godet and the Comité des Yvelines de la Ligue contre le Cancer for their continuous support of this project; M. Pla and the animal housing facility; C. Leboeuf, L. Legrès and A. Janin for facilitation of the pathological analysis of the mice; M. Kawatika, M. Giovanini and F. Riaucoux for the derivation of MRP8-PML-RARAS873A transgenic mice; P. Chambon for the antibody to RARA; S. Kogan for the APLs and the MSCV-luciferase vector; B. Arnulf for bortezomib; H. Tenor (Altana/Nycomed) for piclamilast; O. Hermine and F. Valensi for help with the t(11;17) human data; the Treilles and IPSEN foundations for providing the setting where this work was first presented and developed; and A. Saib, J.C. Gluckman and F. Sigaux for critical reading of the manuscript.

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Author notes

  1. Rihab Nasr

    Present address: Current address: Department of Internal Medicine, American University of Beirut, Bliss Street, P.O. Box 11-0236, Beirut, Lebanon.,

  2. Rihab Nasr and Marie-Claude Guillemin: These authors contributed equally to this work.

Authors and Affiliations

  1. Université de Paris 7/CNRS UMR 7151, Equipe labellisée N°11 Ligue Nationale Contre le Cancer, Service de Biochimie, Hôpital St. Louis, 1, Av. C. Vellefaux, Paris, 75475, CEDEX 10, France

    Rihab Nasr, Marie-Claude Guillemin, Omar Ferhi, Hassan Soilihi, Laurent Peres, Caroline Berthier, Macarena Robledo-Sarmiento, Valérie Lallemand-Breitenbach, Bernard Gourmel, Dominique Vitoux, Jun Zhu & Hugues de Thé

  2. UFR de Médecine Université de Paris 5 & Hematology, Hôpital Mignot, 177 rue de Versailles, Le Chesnay, 78157, France

    Philippe Rousselot

  3. Department of Pathology, Beth Israel Deaconess Medical Center, 77 Avenue Louis Pasteur, Boston, 02115, Massachusetts, USA

    Pier Paolo Pandolfi

  4. Department of Functional Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, BP 10142, Illkirch, F-67400, France

    Cécile Rochette-Egly

  5. CNRS laboratoire associé MPC, Shanghai Institute of Hematology, Rui Jin Hospital, 197 Rui Jin Road, Shanghai, 200025, China

    Jun Zhu & Hugues de Thé

  6. Institut Universitaire de France,

    Hugues de Thé

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Correspondence to Hugues de Thé.

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Competing interests

CNRS UMR7151 has had contacts with ALTANA (now Nycomed), a company that has interest in phosphodiesterase inhibitors (PDEIs). ALTANA provided the authors with piclamilast, a reagent that was use in these studies but does not belong to ALTANA. No financial support was provided toward experiments reported in this study. On the basis of the results reported in this study, Paris 7 University has contracted the testing of another PDEI on the APL animal model used in the study, with financial support from Nycomed to CNRS UMR7151. Paris 7 University has filed a patent to the European patent office for the eradication of LIC through PML-RARA degradation.

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Nasr, R., Guillemin, MC., Ferhi, O. et al. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med 14, 1333–1342 (2008). https://doi.org/10.1038/nm.1891

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