Analysis of common glucocorticoid response genes in childhood acute lymphoblastic leukemia in vivo identifies cell cycle but not apoptosis genes

Abstract

AbstractGlucocorticoids (GCs) are an essential component of acute lymphoblastic leukemia (ALL) therapy. To identify genes mediating the anti-leukemic GC effects in vivo, we performed gene expression profiling of lymphoblasts from 46 children during the first 6-24h of systemic GC mono-therapy. Differential gene expression analysis across all patients revealed a considerable number of GC-regulated genes (190 induced, 179 repressed at 24h). However, when 4 leukemia subtypes (T-ALL, ETV6-RUNX1+, hyperdiploid, other preB-ALLs) were analyzed individually only 17 genes were regulated in all of them showing subtype-specificity of the transcriptional response. “Cell cycle-related” genes were down-regulated in the majority of patients, while no common changes in apoptosis genes could be identified. Surprisingly, none of the cell cycle or apoptosis genes correlated well with the reduction of peripheral blasts used as parameter for treatment response. These data suggest that (a) GC effects on cell cycle are independent of the cell death response and (b) GC-induced cell death cannot be explained by a single transcriptional pathway conserved in all subtypes. To unravel more complex, potentially novel pathways, we employed machine learning algorithms using an iterative elastic net approach, which identified gene expression signatures that correlated with the clinical response.