title: 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.
authors.affiliation: Department of Medicine, SUNY Upstate Medical University, Syracuse, New York 13210, USA. coylet@upstate.edu
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Coyle
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Bair
authors.forename: Constance
authors.initials: C
authors.lastname: Stein
authors.forename: Neerja
authors.initials: N
authors.lastname: Vajpayee
authors.forename: Syed
authors.initials: S
authors.lastname: Mehdi
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wright
mesh_terms: D000208:Acute Disease; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects; D002869:Chromosome Aberrations; D002897:Chromosomes, Human, Pair 7; D002899:Chromosomes, Human, Pair 9; D004249:DNA Damage; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007938:Leukemia / Q000139:chemically induced*; D008297:Male; D014635:Valproic Acid / Q000009:adverse effects*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid