Abstract
BackgroundThe wingless-Int (WNT) pathway has an essential role in cell regulation of hematopoietic stem cells (HSC). For Acute Myeloid Leukemia (AML), the malignant counterpart of HSC, currently only a selective number of genes of the WNT pathway are analyzed by using either gene expression or DNA-methylation profiles for the identification of prognostic markers and potential candidate targets for drug therapy. It is known that mRNA expression is controlled by DNA-methylation and that specific patterns can infer the ability to differentiate biological differences, thus a combined analysis using all WNT annotated genes could provide more insight in the WNT signaling.ApproachWe created a computational approach that integrates gene expression and DNA promoter methylation profiles. The approach represents the continuous gene expression and promoter methylation profiles with nine discrete mutually exclusive scenarios. The scenario representation allows for a refinement of patient groups by a more powerful statistical analysis, and the construction of a co-expression network. We focused on 268 WNT annotated signaling genes that are derived from the molecular signature database.ResultsUsing the scenarios we identified seven prognostic markers for overall survival and event-free survival. Three genes are novel prognostic markers; two with favorable outcome (PSMD2, PPARD) and one with unfavorable outcome (XPNPEP). The remaining four genes (LEF1, SFRP2, RUNX1, and AXIN2) were previously identified but we could refine the patient groups. Three AML risk groups were further analyzed and the co-expression network showed that only the good risk group harbors frequent promoter hypermethylation and significantly correlated interactions with proteasome family members.ConclusionOur results provide novel insights in WNT signaling in AML, we discovered new and previously identified prognostic markers and a refinement of the patient groups.
Highlights
The wingless-Int (WNT) pathway has an essential role in cell regulation of hematopoietic stem cells (HSC)
Analysis of prognostic markers by means of gene-state scenarios It has previously been shown that DNA-methylation or gene expression levels of genes can be used as predictive features to determine clinical outcome of Acute Myeloid Leukemia (AML) patients [6,8]
We speculated that patient groups can be refined when DNA-methylation and gene expression levels of genes are analysed in an integrated fashion
Summary
The wingless-Int (WNT) pathway has an essential role in cell regulation of hematopoietic stem cells (HSC). Wnt3a deficiency leads in leukemia cells to reduced numbers of long-term hematopoietic stem their mRNA expression, thereby deregulation of the WNT signaling The relation between these genetic and epigenetic factors is especially important when studying the disease phenotype, such as for patients with deregulated WNT signaling. Previous studies analysed genetic and epigenetic changes of WNT signaling genes mostly in patients with intermediate risk [6], DNA hypermethylation was found to be enriched for the good risk group [12]. These studies analysed a limited number of genes in the WNT signaling pathway. A comprehensive analysis of the relationships between DNA-methylation and transcript expression by means of all annotated genes of the WNT signaling pathway has not been done
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