Abstract
Alterations of RUNX1 in acute myeloid leukemia (AML) are associated with either a more favorable outcome in the case of the RUNX1/RUNX1T1 fusion or unfavorable prognosis in the case of point mutations. In this project we aimed to identify genes responsible for the observed differences in outcome that are common to both RUNX1 alterations. Analyzing four AML gene expression data sets (n = 1514), a total of 80 patients with RUNX1/RUNX1T1 and 156 patients with point mutations in RUNX1 were compared. Using the statistical tool of mediation analysis we identified the genes CD109, HOPX, and KIAA0125 as candidates for mediator genes. In an analysis of an independent validation cohort, KIAA0125 again showed a significant influence with respect to the impact of the RUNX1/RUNX1T1 fusion. While there were no significant results for the other two genes in this smaller validation cohort, the observed relations linked with mediation effects (i.e., those between alterations, gene expression and survival) were almost without exception as strong as in the main analysis. Our analysis demonstrates that mediation analysis is a powerful tool in the identification of regulative networks in AML subgroups and could be further used to characterize the influence of genetic alterations.
Highlights
Alterations of the Runt-related transcription factor (RUNX1) have been observed to strongly influence the outcome of patients with acute myeloid leukemia (AML)[1]
We demonstrate that, while differential expression is a prerequisite for mediation activity, genes that are differentially expressed are by no means necessarily mediator genes
Using mediation analysis we identified three genes that may help to explain the strong differences in outcome between AML patients with RUNX1 mutations and RUNX1/RUNX1T1 fusions
Summary
Alterations of the Runt-related transcription factor (RUNX1) have been observed to strongly influence the outcome of patients with acute myeloid leukemia (AML)[1]. The observed influences of mutations and fusions on survival are not fully direct, but can be assumed to be in part due to transcriptional deregulation of other genes resulting from alterations of the transcription factor RUNX1 The latter means that the considered alterations have an effect on the expression of these genes and, at the same time, they themselves have an effect on survival independent of the alteration. Mediation analyses are concerned with measuring and testing indirect effects of risk factors of interest on target variables through particular mediator variables Such an analysis is well suited for the main goal of our approach - identifying genes through which RUNX1 mutations and fusions influence the outcome. While there were no significant results for the other two genes in this smaller validation cohort, the observed relations linked with mediation effects (i.e., those between alterations, gene expression and survival) were almost without exception as strong as in the main analysis
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