title: Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL.
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.
authors.affiliation: Institut Universitaire d'Hematologie, Université de Paris 7/Centre National de la Recherche Scientifique Unité Mixte de Recherche 7212/Inserm U944, Equipe labellisée no. 11 Ligue Nationale Contre le Cancer, Hôpital St Louis, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Leiva
authors.forename: S
authors.initials: S
authors.lastname: Moretti
authors.forename: H
authors.initials: H
authors.lastname: Soilihi
authors.forename: I
authors.initials: I
authors.lastname: Pallavicini
authors.forename: L
authors.initials: L
authors.lastname: Peres
authors.forename: C
authors.initials: C
authors.lastname: Mercurio
authors.forename: R
authors.initials: R
authors.lastname: Dal Zuffo
authors.forename: S
authors.initials: S
authors.lastname: Minucci
authors.forename: H
authors.initials: H
authors.lastname: de Thé
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D005434:Flow Cytometry; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D014635:Valproic Acid