Abstract book (download .pdf file) - Redox and Inflammation ...

Valproic Acid perturbs hematopoietic homeostasis by inhibition of erythroid
differentiation and activation of the myelo-monocytic pathway
Sébastien Chateauvieux 1,3 , Serge Eifes 1,3 , Franck Morceau 1 , Christina Grigorakaki 1 ,
Michael Schnekenburger 1 , Estelle Henry 1 , Mario Dicato 2 , Marc Diederich 1 .
1 Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, L-
2540 Luxembourg; 2 Luxembourg Medical Center, Luxembourg, L-1210 Luxembourg;
3 These authors contributed equally
As a histone deacetylase inhibitor, Valproic acid (VPA) is a candidate for anticancer therapy.
Besides, VPA exhibits various mechanisms of action and its effects on the molecular basis of
hematopoiesis remain unclear. To study the effects of VPA on the hematopoietic system, we
performed microarray analysis using K562 cells treated with 1 mM VPA over a 72 h time
course. The association between Gene Ontology (GO) terms and the lists of differentially
expressed genes was tested using the Bioconductor package GOstats. Enrichment analysis for
cellular differentiation pathways was performed based on manually curated gene lists. Results
from microarray analysis were confirmed by studying cell differentiation features at the
molecular and cellular levels using other hematopoietic cell lines as well as hematopoietic
stem/progenitor CD34 + cells. Microarray analysis revealed 3440 modulated genes in the
presence of VPA. Genes involved in the granulo-monocytic differentiation pathway were upregulated
while genes of the erythroid pathway were down-regulated. This was confirmed by
analyzing erythrocytic and myeloid membrane markers and lineage-related gene expression in
HEL, MEG01, HL60 as well as CD34 + cells. Moreover, GATA-1 and its co-factors (FOG1,
SP1) were down-regulated, while myelopoiesis activator PU.1 was up-regulated, in agreement
with an inhibition of erythropoiesis. Our functional profiling and cell phenotyping approach
demonstrates that VPA is able to alter hematopoietic homeostasis by modifying the cell
population balance in the myeloid compartment. This may lead to a potential failure of
erythropoiesis in patients with cancer or chronic inflammatory diseases having a welldescribed
propensity to anemia.
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