Abstract
Aberrant histone acetylation was physiopathologically associated with the development of acute myeloid leukemias (AMLs). Reversal of histone deacetylation by histone deacetylase inhibitor (HDACis) activates a cell death program that allows tumor regression in mouse models of AMLs. We have used several models of PML-RARA-driven acute promyelocytic leukemias (APLs) to analyze the in vivo effects of valproic acid, a well-characterized HDACis. Valproic acid (VPA)-induced rapid tumor regression and sharply prolonged survival. However, discontinuation of treatment was associated to an immediate relapse. In vivo, as well as ex vivo, VPA-induced terminal granulocytic differentiation. Yet, despite full differentiation, leukemia-initiating cell (LIC) activity was actually enhanced by VPA treatment. In contrast to all-trans retinoic acid (ATRA) or arsenic, VPA did not degrade PML-RARA. However, in combination with ATRA, VPA synergized for PML-RARA degradation and LIC eradication in vivo. Our studies indicate that VPA triggers differentiation, but spares LIC activity, further uncouple differentiation from APL clearance and stress the importance of PML-RARA degradation in APL cure.
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Acknowledgements
ML was supported by the Ramon Areces Foundation and currently by a Marie Curie Intra-European Fellowship (under Grant Agreement PIEF-GA-2009-254256). The de Thé laboratory is supported by the Ligue Nationale contre le Cancer, INSERM, CNRS, University Paris Diderot (formerly known as Paris-7), the Institut Universitaire de France, EPITRON (an integrated project funded by the European union under the 6th framework program (LSHC-CT-2005-518417)) and Canceropole programs. Work in the Minucci's group is supported by AIRC, MIUR, MIS and EPITRON. We thank Maria Rosaria Cera, Marco Cirò and Pietro Spinelli for suggestions, discussions and technical help. We thank J Godet and the Comité des Yvelines de la Ligue contre le Cancer for their continuous trust and support.
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SMi and HT designed research and wrote the manuscript; SMo and ML performed research, analyzed and interpreted data and wrote the manuscript; IP collected data; CM analyzed data; and RDZ HS and LP performed experiments.
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Leiva, M., Moretti, S., Soilihi, H. et al. Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL. Leukemia 26, 1630–1637 (2012). https://doi.org/10.1038/leu.2012.39
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DOI: https://doi.org/10.1038/leu.2012.39
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