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

Item Type:	Article
Title:	Molecular dissection of valproic acid effects in acute myeloid leukemia identifies predictive networks
Creators Name:	Rücker, F.G. and Lang, K.M. and Fütterer, M. and Komarica, V. and Schmid, M. and Döhner, H. and Schlenk, R.F. and Döhner, K. and Knudsen, S. and Bullinger, L.
Abstract:	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 in vitro using myeloid cell lines with the idea to integrate findings with in vivo data from AML patients treated with VPA additionally to intensive chemotherapy (n = 12). By gene expression profiling we identified an in vitro VPA response signature enriched for genes/pathways known to be implicated in cell cycle arrest, apoptosis, and DNA repair. Following VPA treatment in vivo, gene expression changes in AML patients showed concordant results with the in vitro 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 in vivo such as CXCR4 and LBH. 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.
Keywords:	Acute Myeloid Leukemia (AML), Gene Expression, Histone Deacetylase Inhibitor (HDACI), MiRNA Expression, Prognostic Marker, Valproic Acid (VPA)
Source:	Epigenetics
ISSN:	1559-2294
Publisher:	Landes Bioscience
Volume:	11
Number:	7
Page Range:	517-525
Date:	2 July 2016
Additional Information:	Copyright © 2016 Taylor & Francis Group, LLC
Official Publication:	https://doi.org/10.1080/15592294.2016.1187350
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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