Endocrine Abstracts

Glucocorticoids (GCs) have an important role in inflammation, apoptosis and immunosuppression and are among the most widely prescribed medications in clinical practice. GCs exert their effect by binding to the transcription factor, glucocorticoid receptor (GR). GCs are used in the treatment of acute lymphoblastic leukaemia (ALL) as they induce apoptosis in lymphoid cells, however resistance and side effects still occur frequently. Computational modeling has enormous potential in the understanding of biological processes such as apoptosis and the discovery of novel regulatory mechanisms.With the advances in high-throughput technology, vast amount of ‘omics’ type of data make the study of drug resistance challenging. Here we use systems biology with the ultimate goal of increasing understanding of GR function and predicting future experimental approaches. As Bcl-2 family of genes that control apoptosis is a key determinant of GC function in ALL, we built kinetic models based on ordinary differential equations that facilitated investigation of the molecular mechanisms of GCs mediated Bim and Bmf induction. To gain a global view on GR resistance in ALL and to extend the previously established models, we performed integrated timecourse microarray analysis in ALL cell lines and clinical samples. This approach identified c-Jun and Erg as crucial determinants of GC resistance and demonstrated that using Erg inhibitors increased apoptosis of ALL cells. Finally, adopting variety of genomewide experimental study designs coupled with specific clustering analysis, we demonstrate that stem cells and bone marrow microenvironment alter expression profiles of genes that control signalling, apoptosis, autophagy and inflammation and increase ALL chemoresistance.

In conclusion, our findings represent a successful example of utilising systems biology to study causes of drug resistance. These approaches aid discovery of biomarkers of GC resistance, advance our understanding of drug sensitivity, link host-tumour interactions to chemoresistance and can be used to improve therapy of leukemia.

Declaration of funding

Children with Cancer UK.

Government of Saudi Arabia.