MicroRNA Screening Reveals Upregulation of FoxO-Signaling in Relapsed Acute Myeloid Leukemia Patients

<b>Background/Objectives</b>: AML is an aggressive malignant disease characterized by aberrant proliferation and accumulation of immature blast cells in the patient's bone marrow. Chemotherapeutic treatment can effectively induce remission and re-establish functional hematopoiesis. However, many patients experience chemoresistance-associated relapse and disease progression with a poor prognosis. The identification of molecular determinants of chemoresistance that could serve as potential targets for the therapeutic restoration of chemosensitivity has proven to be challenging. <b>Methods</b>: To address this, we have analyzed longitudinal changes in the expression of microRNAs during disease progression in a small set of four AML patients, combined with gene ontology (GO) pathway analysis and evaluation of gene expression data in patient databases. <b>Results</b>: MicroRNA profiling of bone marrow samples at diagnosis and after relapse revealed significant differential expression of a large number of microRNAs between the two time points. Subsequent GO pathway analysis identified 11 signal transduction pathways likely to be affected by the differential miRNA signatures. Exemplary validation of the FoxO signaling pathway by gene expression analysis confirmed significant upregulation of <i>FOXO1</i> and the target genes <i>GADD45</i> and <i>SOD2</i>. <b>Conclusions</b>: Here, we show how a microRNA-based pathway prediction strategy can be used to identify differentially regulated signaling pathways that represent potential targets for therapeutic intervention.