Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL

• Published in: Leukemia Vol. 26; no. 7; pp. 1630 - 1637
• Main Authors: Leiva, M, Moretti, S, Soilihi, H, Pallavicini, I, Peres, L, Mercurio, C, Dal Zuffo, R, Minucci, S, de Thé, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2012; Nature Publishing Group
• Subjects: 631/154/436/2388; 631/67/1059/99; 692/699/67/1990/283/1897; Acetylation; Acetylation - drug effects; Acids; Animal models; Animals; Anticonvulsants - pharmacology; Antineoplastic Agents - pharmacology; Arsenic; Biological and medical sciences; Cancer Research; Cell death; Cell differentiation; Cell Differentiation - drug effects; Cell Transformation, Neoplastic - drug effects; Critical Care Medicine; Cytokines; Deacetylation; Degradation; Differentiation; Divalproex; Dosage and administration; Flow Cytometry; Hematologic and hematopoietic diseases; Hematology; Histone deacetylase; Histones; In vivo methods and tests; Intensive; Internal Medicine; Leukemia; Leukemia, Promyelocytic, Acute - drug therapy; Leukemia, Promyelocytic, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Nude; Neoplasm Recurrence, Local; Oncogene Proteins, Fusion - metabolism; Oncology; original-article; Regression; Regression (Disease); Regression analysis; Remission (Medicine); Retinoic acid; Signal Transduction; Tretinoin - pharmacology; Tumor Cells, Cultured; Tumors; Valproic acid; Valproic Acid - pharmacology; Xenograft Model Antitumor Assays; France; Italy; Paris France; retinoic acid; murine models; clonogenic activity; Animal model; Leukemia; Retinoid; Tumor; 4-Aminobutyrate transaminase; Hematology; Enzyme; Transferases; Rodentia; Enzyme inhibitor; Regression; Malignant hemopathy; Valproic acid; Cell differentiation; Biological activity; Transitory; Histone deacetylase inhibitor; Vertebrata; Mammalia; Mouse; Transaminases; Retinoic acid; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2012.39

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.