Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation.

BACKGROUND

The 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 METHODS

We 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.

RESULTS

Trichostatin 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 microM 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.

CONCLUSIONS

Individual histone deacetylase inhibitors 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.