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.
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One reason could be that these agents fail to clear leukaemia-initiating cells (LICs).
“One reason could be that these agents fail to clear leukaemia-initiating cells (LICs) (Leiva et al, 2012).”
From Unlocking the potential of retinoic acid in anticancer therapy (2014) · cites this paper as Leiva et al, 2012
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- Authors
- Leiva, M., Moretti, S., Soilihi, H., Pallavicini, I., Peres, L., Mercurio, C., Dal Zuffo, R., Minucci, S., & de Thé, H.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- European Institute of Oncology (IT)
- University of Milan (IT)
- Venue
- Leukemia
- Published
- 2012-02-15
- Volume
- 26
- Issue
- 7
- Pages
- 1630-1637
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- OpenAlex
- W2062948859
- Cited by
- 58
- References
- 54
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 1 · 2021: 2 · 2019: 3 · 2018: 1 · 2017: 5 · 2016: 9 · 2015: 4 · 2014: 12 · 2013: 7 · 2012: 3
- FWCI
- 3.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Leukemia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission
- Ligue Contre le Cancer
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- valproic acid, acute promyelocytic leukemia, PML-RARA fusion, histone deacetylase inhibitors, leukemia-initiating cells, granulocytic differentiation, tumor regression, relapse, all-trans retinoic acid, arsenic trioxide, histone acetylation, acute myeloid leukemia
- MeSH terms
- Acetylation, Animals, Anticonvulsants, Antineoplastic Agents, Cell Differentiation, Cell Transformation, Neoplastic, Flow Cytometry, Mice, Inbred C57BL, Mice, Nude, Neoplasm Recurrence, Local, Tretinoin, Tumor Cells, Cultured, Valproic Acid, Signal Transduction, Leukemia, Promyelocytic, Acute, Oncogene Proteins, Fusion, Xenograft Model Antitumor Assays, Mice
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