Acute lymphoblastic leukaemia (ALL) of the T-cell lineage (T-ALL) often relapses due to drug resistance to standard-of-care therapies such as glucocorticoids. Children with chemo-resistant T-ALL have a low survival rate of 30-50% and have few therapeutic options. Therefore, a strong unmet need remains to restore glucocorticoid sensitivity and develop more effective therapies. We have recently demonstrated that drug resistance in T-ALL is linked to chromatin closure due to hypermethylation at key DNA regions. We hypothesise that demethylating DNA at these regions will increase chromatin accessibility and reverse glucocorticoid resistance.
Here we demonstrate the in vivo efficacy of a DNA demethylating agent routinely for acute myeloid leukaemia treatment (decitabine) with standard chemotherapy (glucocorticoid dexamethasone) in chemo-resistant T-ALL to extend event-free survival in preclinical models. Three T-ALL patient-derived xenografts (PDXs) were treated with vehicle, decitabine, dexamethasone, or combination to assess decitabine’s action in restoring dexamethasone sensitivity and in vivo efficacy compared to standard preclinical treatment regimen VXL (vincristine, dexamethasone, L-Asparaginase). Upon tracking the leukaemia burden, we observed significantly prolonged survival in both the decitabine and the combination groups compared to the dexamethasone group in all three models. However, the combination group only out-performed decitabine single agent in one model (PDX#5), in which the combination group showed lower efficacy than the VXL group. In the other two models (PDX#2, PDX#15), both decitabine and combination groups demonstrated higher efficacy than the VXL group, but decitabine single agent out-performed the combination group. Global changes in DNA methylation, chromatin accessibility, and transcriptome in each treatment groups were assessed using Illumina methylation EPIC array, ATAC sequencing, and RNA sequencing to identify biomarkers and DNA regulatory mechanisms associated with chemo-resistance in T-ALL and demethylation-induced sensitisation to glucocorticoid. Consistent with the in vivo efficacy results, dexamethasone antagonised the demethylating action of decitabine in models PDX#2 and PDX#15, while this antagonising effect was not observed in model PDX #5. These findings demonstrate a clear link between epigenetic alterations and chemotherapy response and provide foundation for repurposing decitabine to treat children with chemo-resistant T-ALL.