NFκB modulators in a model of glucocorticoid resistant, childhood acute lymphoblastic leukemia

Glucocorticoids (GCs) are pivotal agents in the treatment of childhood acute lymphoblastic leukaemia (ALL) but the molecular basis of GC-resistance remains unclear. Expression-array studies have shown that commonly upregulated genes associated with GC-sensitivity include GR, glucocorticoid-induced leucine zipper (GILZ) and IκBα, which all negatively interact with components of the pro-survival NFκB pathway and therefore may be critical determinants of GC-sensitivity. We have investigated these regulators and their effect on NFκB activity in GC-resistant descendents of the B-lineage ALL cell line, PreB 697. We show that while differential up regulation of the modulators (GILZ, GR and IκBα) was demonstrated in GC-sensitive compared to GC-resistant sub-lines, this was not coupled with altered nuclear translocation or functionality of the RelA, p50 or c-Rel subunits of NFκB. Thus, GC-resistance in the PreB 697 cell line model is not mediated by NFκB, however further investigation of the impact of these GC-sensitive associated proteins on other survival pathways, such as the RAS-RAF-MEK-ERK pathway, is warranted.