Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation

Abstract

The online version of this article has a Supplementary Appendix. BackgroundThe clinical use of chromatin-modulating drugs, such as histone deacetylase inhibitors, for the treatment of bone marrow failure and hematopoietic malignancies has increased dramatically over the last few years. Nonetheless, little is currently known concerning their effects on myelopoiesis. Design and MethodsWe utilized an ex vivo differentiation system in which umbilical cord blood-derived CD34 + cells were treated with trichostatin A, sodium butyrate and valproic acid to evaluate the effect of histone deacetylase inhibitor treatment on myeloid lineage development, colony-forming potential, proliferation, and terminal neutrophil differentiation. ResultsTrichostatin A treatment modestly reduced progenitor proliferation, while sodium butyrate and valproic acid resulted in concentration-dependent effects on proliferation and apoptosis. Addition of valproic acid uniquely stimulated CD34 + proliferation. Sodium butyrate treatment inhibited terminal neutrophil differentiation both quantitatively and qualitatively. Addition of 100 μM valproic acid resulted in increased numbers of mature neutrophils with a block in differentiation at increasing concentrations. Sodium butyrate and valproic acid treatment resulted in increased acetylation of histones 3 and 4 while trichostatin A, sodium butyrate and valproic acid had differential effects on the acetylation of non-histone proteins. ConclusionsIndividual histone deacetylase inihibitors had specific effects on cell fate decisions during myeloid development. These data provide novel insights into the effects of histone deacetylase inhibitors on the regulation of normal hematopoiesis, which is of importance when considering utilizing these compounds for the treatment of myeloid malignancies and bone marrow failure syndromes.Key words: hematopoiesis, HDAC inhibitors, neutrophil. Haematologica 2010;95:1052-1060. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Bartels M, Geest CR, Bierings M, Buitenhuis M, and Coffer PJ. Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation. Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation

Acetylation of C/EBPε is a prerequisite for terminal neutrophil differentiation

“…We have previously demonstrated that modulating protein acetylation in CD34 1 hematopoietic progenitors, by using lysine deacetylase inhibitors (KDACi), affects cell fate decisions during myeloid development. 35 These data suggested that the effects were the result of regulation of both histone and nonhistone proteins. Skokowa et al have demonstrated that treatment of myeloid progenitors with NAM stimulates neutrophil differentiation both in vitro and in vivo.…”

“…Modulating acetylation by NAM or other KDACi could therefore be of importance for the treatment of neutropenia or functional neutrophil defects. 32,35,41 …”

“…35 Bicistronic retroviral DNA constructs were used, expressing the gene of interest (C/EBPe, C/EBPe K121/198R, C/EBPe R121/ 198K, and C/EBPe K15xR) and an internal ribosomal entry site, followed by the gene encoding for green fluorescent protein (eGFP). Retroviral transductions were performed as previously described.…”

Sodium butyrate restores ASC expression and induces apoptosis in LS174T cells

“…Gene silencing associated with the aberrant methylation of promoter region of CpG islands is an acquired epigenetic alteration that serves as an alternative to genetic events in the inactivation of tumor suppressor and other genes in human cancers. NaBu has been applied in cellular and molecular research (23,24), particularly in antitumor research (25)(26)(27)(28). It plays a vital role in vitamin D-induced apoptosis through PTEN upregulation, which has potential benefit in gastric cancer therapy (29).…”

In Vivo Chemical Screen in Zebrafish Embryos Identifies Regulators of Hematopoiesis Using a Semiautomated Imaging Assay

“…VPA was reported to induce the expansion of CD34 + progenitors in mice in a concentration-dependent manner. 27 Furthermore, colonyforming units-spleen (CFU-S) assays and competitive repopulation assays showed that VPA increases proliferation as well as self-renewal of HSCs. 16 Here, we show that VPA increases the population of CD34 + CD90 + significantly.…”