title: Valproic acid triggers erythro/megakaryocyte lineage decision through induction of GFI1B and MLLT3 expression.
abstract: Histone deacetylase inhibitors represent a family of targeted anticancer compounds that are widely used against hematological malignancies. So far little is known about their effects on normal myelopoiesis. Therefore, in order to investigate the effect of histone deacetylase inhibitors on the myeloid commitment of hematopoietic stem/progenitor cells, we treated CD34(+) cells with valproic acid (VPA). Our results demonstrate that VPA treatment induces H4 histone acetylation and hampers cell cycle progression in CD34(+) cells sustaining high levels of CD34 protein expression. In addition, our data show that VPA treatment promotes erythrocyte and megakaryocyte differentiation. In fact, we demonstrate that VPA treatment is able to induce the expression of growth factor-independent protein 1B (GFI1B) and of mixed-lineage leukemia translocated to chromosome 3 protein (MLLT3), which are crucial regulators of erythrocyte and megakaryocyte differentiation, and that the up-regulation of these genes is mediated by the histone hyperacetylation at their promoter sites. Finally, we show that GFI1B inhibition impairs erythroid and megakaryocyte differentiation induced by VPA, while MLLT3 silencing inhibits megakaryocyte commitment only. As a whole, our data suggest that VPA sustains the expression of stemness-related markers in hematopoietic stem/progenitor cells and is able to interfere with hematopoietic lineage commitment by enhancing erythrocyte and megakaryocyte differentiation and by inhibiting the granulocyte and mono-macrophage maturation.
authors.affiliation: Centre for Regenerative Medicine, Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Zini
authors.forename: Ruggiero
authors.initials: R
authors.lastname: Norfo
authors.forename: Francesco
authors.initials: F
authors.lastname: Ferrari
authors.forename: Elisa
authors.initials: E
authors.lastname: Bianchi
authors.forename: Simona
authors.initials: S
authors.lastname: Salati
authors.forename: Valentina
authors.initials: V
authors.lastname: Pennucci
authors.forename: Giorgia
authors.initials: G
authors.lastname: Sacchi
authors.forename: Chiara
authors.initials: C
authors.lastname: Carboni
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Ceccherelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Tagliafico
authors.forename: Sergio
authors.initials: S
authors.lastname: Ferrari
authors.forename: Rossella
authors.initials: R
authors.lastname: Manfredini
mesh_terms: D000107:Acetylation / Q000187:drug effects; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D041905:Erythroid Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000235:genetics*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018952:Antigens, CD34; D002843:Chromatin; D050989:GATA2 Transcription Factor; C111977:GFI1B protein, human; D006657:Histones; C489901:MLLT3 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014635:Valproic Acid