In vivo resistance to dexamethasone in a model of acute lymphoblastic leukaemia

Although paediatric acute lymphoblastic leukaemia (ALL) has a favourable prognosis, relapsed disease does not have such good survival rates. The development of drug resistance is one of the major problems associated with relapsed ALL and the underlying reasons are not well understood.

The pre B ALL cell line 697 (t(1;19)) is a good model to study glucocorticoid (GC) sensitivity in vitro as unlike many other ALL cell lines the 697 cells are sensitive to dexamethasone (dex) (IC50˜20nM). However, when we transplanted NSG mice with 697 cells, this sensitivity did not translate into increased survival despite reaching plasma concentrations of dex at 6hrs 150x the IC50 of 697 cells in vitro. Importantly, when analysing cytotoxicity and cell cycle distribution we found no difference in dex sensitivity between xenograft material (dex treated and control) and the parental cell line, indicating that the 697 xenograft cells were GC sensitive in vitro.

We are currently performing RNA sequencing on xenograft and in vitro samples in order to identify gene expression signatures associated with Dex resistance in vivo. The outcome of this study has significant implications for patients with GC resistance not associated with loss of NR3C1 or mutations affecting cell survival.