Acute leukemia associated with valproic acid treatment: A novel mechanism for leukemogenesis?

Abstract

Valproic acid has been previously associated with hematologic toxicity, including a reversible myelodysplasia-like syndrome without chromosomal abnormalities. We now report three cases of acute leukemia with features of secondary leukemia associated with valproic acid therapy: two cases of acute myelogenous leukemia with multilineage dysplasia, one with trisomy 8 and one with monosomy 7, and one case of secondary acute lymphoblastic leukemia with del (7) (q22q34), del (9) (q21.11q22), del (11) (q12q23). One patient had a previous myelodysplastic syndrome while on valproic acid. Valproic acid has been previously shown to be a histone deacetylase inhibitor. Inhibition of histone deacetylase causes a relaxation of chromatin structure and thus increases susceptibility to DNA damage and sensitizes cells to radiation. We propose that valproic acid therapy may lead to secondary leukemia by increasing DNA damage through chronic inhibition of histone deacetylase. Am.

Cancer Risk in Long-term Users of Valproate: A Population-Based Case-Control Study

“…However, the demethylation activity of valproate has not been confirmed by other groups. It has been reported that patients treated with valproate may develop overt acute leukemia (32,33).…”

Valproic Acid Increases Conservative Homologous Recombination Frequency and Reactive Oxygen Species Formation: A Potential Mechanism for Valproic Acid-Induced Neural Tube Defects

“…Further evidence indicates that valproic acid may contribute to genomic instability, because a growing body of evidence demonstrates that valproic acid alters chromatin structure because it can function as a histone deacetylase inhibitor, leading to the acetylation of histone tails (Marchion et al, 2005). This change in the chromatin structure relaxes the conformation of DNA, making it more susceptible to DNA damage, including double-strand breaks (Coyle et al, 2005). Valproic acid's histone deacetylase activity has been attributed to certain pathologies, including valproic acidinduced teratogenesis and valproic acid-associated acute leu- Fig.…”

“…at ASPET Journals on May 12, 2018 molpharm.aspetjournals.org kemia, and is the basis behind the current testing of the effectiveness of valproic acid in cancer therapy (Phiel et al, 2001;Camphausen et al, 2005;Coyle et al, 2005).…”

Valproic acid exhibits biphasic effects on apoptotic cell death of activated lymphocytes through differential modulation of multiple signaling pathways

“…The reason is because it can function as a HDAC inhibitor, leading to the acetylation of histone tails (Marchion et al, 2005) and the relaxing of chromatin, thus making it more susceptible to DNA damage, including DSBs (Coyle et al, 2005). It has been shown that phosphorylated histone H2A.X (γH2A.X) is an early marker of DNA DSBs that can lead to altered gene expression and induction of apoptosis (Coyle et al, 2005;Marchion et al, 2005). HDAC activities should be effectively blocked by VPA as revealed by histone H3 acetylation.…”