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.


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 microg/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.
Liu
Bing
B
Mie University Graduate School of Medicine, Japan.
Ohishi
Kohshi
K
Yamamura
Kentaro
K
Suzuki
Kei
K
Monma
Fumihiko
F
Ino
Kazuko
K
Nishii
Kazuhiro
K
Masuya
Masahiro
M
Sekine
Takao
T
Heike
Yuji
Y
Takaue
Yoichi
Y
Katayama
Naoyuki
N
D018952:Antigens, CD34; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism*; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology*; D050982:GATA1 Transcription Factor / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology*; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013234:Stem Cells; D034061:Thrombopoiesis / Q000187:drug effects*; D013926:Thrombopoietin / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology*
D018952:Antigens, CD34; D018682:GABA Agents; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C508596:IL3 protein, human; C061248:ITGB3 protein, human; D039661:Integrin beta3; D007377:Interleukin-3; D012333:RNA, Messenger; D004921:Erythropoietin; D014635:Valproic Acid; D013926:Thrombopoietin