Molecular dissection of valproic acid effects in acute myeloid leukemia identifies predictive networks.
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.
a Department of Internal Medicine III , University Hospital of Ulm , Ulm , Germany.
Frank G
FG
Rücker
a Department of Internal Medicine III , University Hospital of Ulm , Ulm , Germany.
Katharina M
KM
Lang
a Department of Internal Medicine III , University Hospital of Ulm , Ulm , Germany.
Markus
M
Fütterer
a Department of Internal Medicine III , University Hospital of Ulm , Ulm , Germany.
Vladimir
V
Komarica
b Department of Medical Oncology and Hematology , Triemli Hospital , Zurich , Switzerland.
Mathias
M
Schmid
a Department of Internal Medicine III , University Hospital of Ulm , Ulm , Germany.
Hartmut
H
Döhner
a Department of Internal Medicine III , University Hospital of Ulm , Ulm , Germany.
Richard F
RF
Schlenk
a Department of Internal Medicine III , University Hospital of Ulm , Ulm , Germany.
Konstanze
K
Döhner
c Medical Prognosis Institute (MPI) , Hørsholm , Denmark.
Steen
S
Knudsen
a Department of Internal Medicine III , University Hospital of Ulm , Ulm , Germany.
Lars
L
Bullinger
D000328:Adult; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000235:genetics; D053263:Gene Regulatory Networks / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D019718:Receptors, CXCR4 / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors; D059467:Transcriptome; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
C527276:CXCR4 protein, human; D056572:Histone Deacetylase Inhibitors; C531176:LBH protein, human; D035683:MicroRNAs; D019718:Receptors, CXCR4; D015534:Trans-Activators; D014157:Transcription Factors; D014635:Valproic Acid
Acute myeloid leukemia (AML); gene expression; histone deacetylase inhibitor (HDACI); miRNA expression; prognostic marker; valproic acid (VPA)