Molecular dissection of valproic acid effects in acute myeloid leukemia identifies predictive networks

<p>Histone deacetylase inhibitors (HDACIs) like valproic acid (VPA) display activity in leukemia models and induce tumor-selective cytotoxicity against acute myeloid leukemia (AML) blasts. As there are limited data on HDACIs effects, we aimed to dissect VPA effects <i>in vitro</i> using myeloid cell lines with the idea to integrate findings with <i>in vivo</i> data from AML patients treated with VPA additionally to intensive chemotherapy (n = 12). By gene expression profiling we identified an <i>in vitro</i> VPA response signature enriched for genes/pathways known to be implicated in cell cycle arrest, apoptosis, and DNA repair. Following VPA treatment <i>in vivo</i>, gene expression changes in AML patients showed concordant results with the <i>in vitro</i> VPA response despite concomitant intensive chemotherapy. Comparative miRNA profiling revealed VPA-associated miRNA expression changes likely contributing to a VPA-induced reversion of deregulated gene expression. In addition, we were able to define markers predicting VPA response <i>in vivo</i> such as <i>CXCR4</i> and <i>LBH</i>. These could be validated in an independent cohort of VPA and intensive chemotherapy treated AML patients (n = 114) in which they were inversely correlated with relapse-free survival. In summary, our data provide new insights into the molecular mechanisms of VPA in myeloid blasts, which might be useful in further advancing HDAC inhibition based treatment approaches in AML.</p>