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Pathways of retinoic acid- or arsenic trioxide-induced PML/RARα catabolism, role of oncogene degradation in disease remission

Abstract

Although there is evidence to suggest that PML/RARα expression is not the sole genetic event required for the development of acute promyelocytic leukemia (APL), there is little doubt that the fusion protein plays a central role in the initiation of leukemogenesis. The two therapeutic agents, retinoic acid and arsenic, that induce clinical remissions in APL, both target the oncogenic fusion protein, representing the first example of oncogene-directed cancer therapy. This review focuses on the molecular mechanisms accounting for PML/RARα degradation. Each drug targets a specific moiety of the fusion protein (RARα for retinoic acid, PML for arsenic) to the proteasome. Moreover, both activate a common caspase-dependent cleavage in the PML part of the fusion protein. Specific molecular determinants (the AF2 transactivator domain of RARα for retinoic acid and the K160 SUMO-binding site in PML for arsenic) are respectively implicated in RA- or arsenic-triggered catabolism. The respective roles of PML/RARα activation versus its catabolism are discussed with respect to differentiation or apoptosis induction in the context of single or dual therapies.

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Acknowledgements

We thank many colleagues for insightful discussions and the Treilles Foundation for providing the appropriate setting for this work to mature. Work in our laboratory is supported by Ligue contre le cancer, ARC, Fondation de France, Eli Lilly and EEC.

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Correspondence to Hugues de Thé.

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Zhu, J., Lallemand-Breitenbach, V. & de Thé, H. Pathways of retinoic acid- or arsenic trioxide-induced PML/RARα catabolism, role of oncogene degradation in disease remission. Oncogene 20, 7257–7265 (2001). https://doi.org/10.1038/sj.onc.1204852

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