Deficient histone acetylation in acute leukemia and the correction by an isothiocyanate.

ABSTRACT

OBJECTIVE: Since histone hypoacetylation due to excess histone deacetylases (HDACs) has been associated with transcriptional repression in leukemia, we aimed to determine deficient histone acetylation in patients with acute leukemia and the effect of its correction by an isothiocyanate. METHODS: The acetylation status of histones H3 and H4 in cells from patients with untreated acute leukemia was determined by Western blot. Deficient histone acetylation was analyzed in relation to the disease state. Bone marrow cells from 10 patients with acute myeloid leukemia (AML) were cultured in phenylhexyl isothiocyanate (PHI) to evaluate correction of the deficiency. RESULTS: Acetylation of histones H3 and H4 was virtually undetectable or significantly lower in acute leukemia. This deficiency was consistent among all the patients examined. Histone acetylation was up-regulated in the presence of PHI, revealing an excess of deacetylation activity in AML. PHI treatment induced apoptosis, indicating HDAC inhibition was able to correct the deficiency. CONCLUSIONS: Deficient histone acetylation may represent an aberration at the epigenetic level in acute leukemia. PHI might represent a target for correcting deficient acetylation, and potential epigenetic regulators for preventing the progression of leukemia.