Acute Leukemia Associated with Valproic Acid Treatment: A Novel Mechanism for Leukemogenesis?.

Valproic acid (VA) is the most commonly used antiepileptic drug. It has a wide spectrum of hematologic toxicity including thrombocytopenia, anemia, leukopenia, macrocytosis and the presence of the Pelger-Huet abnormality. Serious but reversible hematologic toxicity resembling a myelodysplastic syndrome (MDS) has also been reported. In these cases, cytogenetics, when tested, was normal and progression to acute leukemia was not reported. We now report three cases of acute leukemia associated with VA therapy, accompanied by cytogenetic abnormalities and features suggestive of secondary leukemia. Three patients were recognized as having acute leukemia associated with VA at a single institution over an eight-year period. All three cases had characteristics of secondary acute leukemia. Two had Acute Myelogenous Leukemia (AML) with multilineage dysplasia (one patient with monosomy 7 and one with trisomy 8) and one had Acute Lymphocytic Leukemia (ALL)(partial deletions of chromosome 7, 9, and 11, with a breakpoint at 11q23). One patient with AML had a recognized preceeding myelodysplastic syndrome with normal cytogenetics that acquired trisomy 8 at progression. All three patients had no other risk factors for secondary leukemia. Two patients had been treated with VA for Lenox-Gaustat syndrome for > 20 years and 2 years, and one was treated for idiopathic epilepsy for > 15 years.

The leukemogenic mechanism for secondary leukemia is thought to be DNA damage from radiation, chemotherapy drugs, organic solvents or inability to repair such damage from genetic defects in DNA repair enzymes. Chromatin is a dynamic structure and changes in it regulate multiple processes. It is modified through post-translational modifications of the DNA binding histone proteins, including acetylation of lysinses on the tails of histone proteins. Histone acetylation is associated with gene expression and deacetylation is associated with inhibition of gene expression. DNA in chromatin that has a relaxed conformation due to increased histone acetylation is more susceptible to DNA damage by radiation. VA was recently shown to be an inhibitor of histone deacetylase (HDAC). It causes hypereacetylation of histones in cultured cells and relieves HDAC induced transcriptional repression. These findings suggest a novel mechanism of leukemogenesis by VA. We hypothesize that chronic HDAC inhibition by VA results in hyperacetylation of chromatin and relaxation in chromatin structure. This, in turn, may cause increased sensitivity to double-stranded DNA breaks caused by low-level exposure to radiation, exogneous chemicals, or perhaps by cellular oxidant stress. Alternatively, chronic inhibition of HDAC may decrease the ability to repair DNA damage. The resultant DNA damage may subsequently lead to leukemogenesis through several genetic pathways. Interestingly, VA is being studied as a potential treatment for leukemia and MDS and it has been shown to induce expression of silenced tumor suppressor genes, and cause differentiation and/or apoptosis of leukemia cell lines in vitro. The fact that VA may have therapeutic effects in some cases of leukemia is, however, not incompatible with it also being potentially leukemogenic. Further study is needed to better define the incidence and mechanism of VA associated acute leukemia.