期刊
LEUKEMIA
卷 26, 期 7, 页码 1630-1637出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2012.39
关键词
clonogenic activity; retinoic acid; murine models
资金
- Ramon Areces Foundation
- Marie Curie Intra-European Fellowship [PIEF-GA-2009-254256]
- Ligue Nationale contre le Cancer
- INSERM
- CNRS
- University Paris Diderot
- Institut Universitaire de France
- EPITRON
- European union [LSHC-CT-2005-518417]
- Canceropole program
- AIRC
- MIUR
- MIS
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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