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

• Published in: Experimental hematology Vol. 38; no. 8; pp. 685 - 695
• Main Authors: Liu, Bing, Ohishi, Kohshi, Yamamura, Kentaro, Suzuki, Kei, Monma, Fumihiko, Ino, Kazuko, Masuya, Masahiro, Sekine, Takao, Heike, Yuji, Takaue, Yoichi, Katayama, Naoyuki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2010
• Subjects: Advanced Basic Science; Antigens, CD34; Erythroid Precursor Cells - cytology; Erythroid Precursor Cells - metabolism; Erythropoiesis - drug effects; Erythropoietin - pharmacology; GABA Agents - pharmacology; GATA1 Transcription Factor - metabolism; GATA2 Transcription Factor - metabolism; Gene Expression Regulation - drug effects; Hematology, Oncology and Palliative Medicine; Humans; Integrin beta3 - metabolism; Interleukin-3 - pharmacology; Megakaryocytes - cytology; Megakaryocytes - metabolism; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - metabolism; RNA, Messenger - metabolism; Stem Cells; Thrombopoiesis - drug effects; Thrombopoietin - pharmacology; Valproic Acid - pharmacology
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2010.03.019

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.