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

Glucocorticoids (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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Austrian Science Fund (SFB021 and W1101-P13 and P6) and a grant from the Cancer Aid Society Tirol. The Tyrolean Cancer Research Institute is supported by the Tirol Kliniken GmbH and the Tyrolean Cancer Aid Society. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approved by the Ethics Committee of Innsbruck Medical University (EK1-1193-172/35) with written informed consent obtained from parents or custodians All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Raw and preprocessed expression data has been deposited at the Gene Expression Omnibus (Accession number: GSE73578); during review process the data is accessible using the link: . .