BMSEHA15
Published online 27 January 2010
(Haematologica 2010, 10.3324/haematol.2009.008870)
Copyright © 2010 by Ferrata Storti Foundation
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Article

Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation

Marije Bartels1,2, Christian R. Geest1, Marc Bierings2, Miranda Buitenhuis1, Paul J. Coffer1,3

1 Molecular Immunology Lab, Dept of Immunology, University Medical Center, Utrecht, the Netherlands
2 Dept. of Pediatric Hematology/Oncology, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, the Netherlands
3 Dept. of Pediatric Immunology, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, the Netherlands

Correspondence: Paul J. Coffer, Molecular Immunology Lab, Depts. of Immunology & Pediatric Immunology, University Medical Center, Lundlaan 6, 3584 EA Utrecht, The Netherlands. Phone: international +31.88.7557674. Fax: international +31.88.7554305. E-mail: p.j.coffer{at}umcutrecht.nl

ABSTRACT

Background: The clinical use of chromatin modulating drugs, such as histone deacetylase (HDAC) 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 Methods: We utilized an ex-vivo differentiation system in which umbilical cord blood derived CD34+ cells were treated with trichostatin A (TSA), sodium butyrate (SB) and valproic acid (VPA) to evaluate the effect of HDAC inhibitor treatment on myeloid lineage development, colony-forming potential, proliferation, and terminal neutrophil differentiation.

Results: TSA treatment modestly reduced progenitor proliferation, while SB and VPA resulted in concentration dependent effects on proliferation and apoptosis. Addition of VPA uniquely stimulated CD34+ proliferation. SB treatment both quantitatively and qualitatively inhibited terminal neutrophil differentiation. Addition of 100mM VPA resulted in increased numbers of mature neutrophils with a block in differentiation at increasing concentrations. SB and VPA treatment resulted in increased histone (H)-3- and H4-acetylation and TSA, SB and VPA have differential effects on the acetylation of non-histone proteins.

Conclusions: Individual HDAC inihibitor treatment has specific effects on cell fate decisions during myeloid development. These data provide novel insights in the effects of HDAC inhibitors on regulation of normal hematopoiesis, which is of importance when considering utilizing these compounds for the treatment of myeloid malignancies and bone marrow failure syndromes.