A potential activity of valproic acid in the stimulation of interleukin-3−mediated megakaryopoiesis and erythropoiesis

Objective

Although the anticancer activities of histone deacetylase (HDAC) inhibitors have been studied, a role for HDAC in normal hematopoiesis has not been clearly defined. Previous studies have shown that the potent HDAC inhibitor FK228 stimulates interleukin (IL)-3−mediated erythropoiesis. Here, we examined whether the widely used valproic acid (VPA) affects megakaryopoiesis as well as erythropoiesis.

Materials and Methods

CD34⁺ cells were incubated in serum-free or serum-containing cultures with cytokines, with or without VPA.

Results

In the serum-free cultures containing IL-3+stem cell factor (SCF), VPA significantly increased generation of CD61⁺GPA⁻ megakaryocytic and a CD61⁺GPA⁺ mixture of megakaryocytic and erythroid precursors from CD34⁺ hematopoietic precursors at a pharmacological concentration (100 μg/mL). The increase in generation of megakaryocytic and erythroid precursors by VPA was confirmed by replating cultured cells with thrombopoietin+SCF and erythropoietin+SCF, respectively. VPA was as potent as FK228. In cultures with granulocyte-macrophage colony-stimulating factor+SCF, where CD61⁻GPA⁺ erythroid precursors were mostly developed, VPA mainly enhanced the generation of CD61⁻GPA⁺ erythroid precursors. In serum-containing cultures, only low numbers of CD61⁺ or GPA⁺ cells were developed with IL-3+SCF. Nevertheless, a substantial number of these cells were generated with VPA. Furthermore, these stimulating effects of VPA were observed by incubating CD34⁺ cells from patients with myelodysplastic syndrome. Quantitative reverse transcription polymerase chain reaction showed that VPA enhanced GATA-2, but not GATA-1, messenger RNA expression with IL-3+SCF.

Conclusions

These results indicate a novel role for VPA in enhancing the potential of IL-3 to stimulate megakaryopoiesis as well as erythropoiesis and suggest a new therapeutic approach of epigenetic therapy for hematological disease.