title: Valproic acid stimulates proliferation and self-renewal of hematopoietic stem cells.
abstract: Histone deacetylase inhibitors have attracted considerable attention because of their ability to overcome the differentiation block in leukemic blasts, an effect achieved either alone or in combination with differentiating agents, such as all-trans retinoic acid. We have previously reported favorable effects of the potent histone deacetylase inhibitor valproic acid in combination with all-trans retinoic acid in patients with advanced acute myeloid leukemia leading to blast cell reduction and improvement of hemoglobin. These effects were accompanied by hypergranulocytosis most likely due to an enhancement of nonleukemic myelopoiesis and the suppression of malignant hematopoiesis rather than enforced differentiation of the leukemic cells. These data prompted us to investigate the effect of valproic acid on normal hematopoietic stem cells (HSC). Here we show that valproic acid increases both proliferation and self-renewal of HSC. It accelerates cell cycle progression of HSC accompanied by a down-regulation of p21(cip-1/waf-1). Furthermore, valproic acid inhibits GSK3beta by phosphorylation on Ser9 accompanied by an activation of the Wnt signaling pathway as well as by an up-regulation of HoxB4, a target gene of Wnt signaling. Both are known to directly stimulate the proliferation of HSC and to expand the HSC pool. In summary, we here show that valproic acid, known to induce differentiation or apoptosis in leukemic blasts, stimulates the proliferation of normal HSC, an effect with a potential effect on its future role in the treatment of acute myeloid leukemia.
authors.affiliation: Medizinische Klinik II/Abteilung Hämatologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany.
authors.forename: Gesine
authors.initials: G
authors.lastname: Bug
authors.forename: Hilal
authors.initials: H
authors.lastname: Gül
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schwarz
authors.forename: Heike
authors.initials: H
authors.lastname: Pfeifer
authors.forename: Manuela
authors.initials: M
authors.lastname: Kampfmann
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zheng
authors.forename: Tim
authors.initials: T
authors.lastname: Beissert
authors.forename: Simone
authors.initials: S
authors.lastname: Boehrer
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Oliver Gerhard
authors.initials: OG
authors.lastname: Ottmann
authors.forename: Martin
authors.initials: M
authors.lastname: Ruthardt
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D014157:Transcription Factors; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018952:Antigens, CD34; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C090460:HOXB4 protein, human; D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D014157:Transcription Factors; D014212:Tretinoin; D014635:Valproic Acid; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3