Acute lymphoblastic leukaemia (ALL) is the most common form of cancer in
children. Despite significant improvements in the treatment of childhood T-cell
ALL (T-ALL), as many as 30% of patients relapse and face a dismal prognosis.
Resistance to glucocorticoids (GC) is known to be a major factor contributing
to the poor prognosis of relapsed T-ALL. However, the mechanisms involved in GC
resistance are poorly understood. Utilising a unique panel of GC-resistant and
sensitive T-ALL cell lines we performed gene expression profiling to
investigate molecular changes underpinning the resistant phenotype. These
studies revealed distinct differences between resistant and sensitive T-ALL
cell lines. Gene set enrichment analysis (GSEA) associated cellular metabolism
pathways including glycolysis, oxidative phosphorylation and cholesterol
biosynthesis, with GC resistance. Combined use of the GC methylprednisolone (Mpred) and
the oxidative phosphorylation inhibitor oligomycin was able to overcome GC
resistance in vitro, as was the
combination of Mpred and the cholesterol synthesis inhibitor simvastatin. Our
results indicate that T-ALL cells are able to switch between bioenergetic
pathways in response to cellular cues such as nutrient and pharmacological
exposure, and that concomitant inhibition of multiple components of cellular
energy pathways is a promising treatment strategy to overcome GC-resistance
in T-ALL cells